Gene Summary

Gene:RBL2; RB transcriptional corepressor like 2
Aliases: Rb2, P130
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:retinoblastoma-like protein 2
Source:NCBIAccessed: 31 August, 2019


What does this gene/protein do?
Show (15)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 31 August 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Endometrial Cancer
  • Neuroblastoma
  • Melanoma
  • Cell Cycle Proteins
  • Nasopharyngeal Cancer
  • Tumor Suppressor Gene
  • Transcription
  • Molecular Sequence Data
  • DNA Mutational Analysis
  • Gene Expression Profiling
  • Cell Proliferation
  • Mutation
  • DNA Methylation
  • Tumor Virus Infections
  • Retinoblastoma-Like Protein p130
  • Promoter Regions
  • T-Lymphocytes
  • Immunohistochemistry
  • Thrombocytosis
  • Transfection
  • Genes, Retinoblastoma
  • Transcription Factors
  • Cancer DNA
  • RB1
  • Down-Regulation
  • Cell Cycle
  • Urinary Tract
  • Trinucleotide Repeats
  • Signal Transduction
  • Sequence Homology
  • Phosphoproteins
  • Proteins
  • Retinoblastoma
  • Base Sequence
  • RBL1
  • Chromosome 16
  • Xenograft Models
  • Survival Rate
  • Lung Cancer
  • DNA-Binding Proteins
  • Nuclear Proteins
  • Cancer Gene Expression Regulation
  • Cell Differentiation
Tag cloud generated 31 August, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (7)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: RBL2 (cancer-related)

Starrett GJ, Serebrenik AA, Roelofs PA, et al.
Polyomavirus T Antigen Induces
MBio. 2019; 10(1) [PubMed] Free Access to Full Article Related Publications
APOBEC3B is a single-stranded DNA cytosine deaminase with beneficial innate antiviral functions. However, misregulated APOBEC3B can also be detrimental by inflicting APOBEC signature C-to-T and C-to-G mutations in genomic DNA of multiple cancer types. Polyomavirus and papillomavirus oncoproteins induce APOBEC3B overexpression, perhaps to their own benefit, but little is known about the cellular mechanisms hijacked by these viruses to do so. Here we investigate the molecular mechanism of APOBEC3B upregulation by the polyomavirus large T antigen. First, we demonstrate that the upregulated APOBEC3B enzyme is strongly nuclear and partially localized to virus replication centers. Second, truncated T antigen (truncT) is sufficient for APOBEC3B upregulation, and the RB-interacting motif (LXCXE), but not the p53-binding domain, is required. Third, genetic knockdown of RB1 alone or in combination with RBL1 and/or RBL2 is insufficient to suppress truncT-mediated induction of

Singh HP, Wang S, Stachelek K, et al.
Developmental stage-specific proliferation and retinoblastoma genesis in RB-deficient human but not mouse cone precursors.
Proc Natl Acad Sci U S A. 2018; 115(40):E9391-E9400 [PubMed] Free Access to Full Article Related Publications
Most retinoblastomas initiate in response to the inactivation of the

Iness AN, Felthousen J, Ananthapadmanabhan V, et al.
The cell cycle regulatory DREAM complex is disrupted by high expression of oncogenic B-Myb.
Oncogene. 2019; 38(7):1080-1092 [PubMed] Free Access to Full Article Related Publications
Overexpression of the oncogene MYBL2 (B-Myb) is associated with increased cell proliferation and serves as a marker of poor prognosis in cancer. However, the mechanism by which B-Myb alters the cell cycle is not fully understood. In proliferating cells, B-Myb interacts with the MuvB core complex including LIN9, LIN37, LIN52, RBBP4, and LIN54, forming the MMB (Myb-MuvB) complex, and promotes transcription of genes required for mitosis. Alternatively, the MuvB core interacts with Rb-like protein p130 and E2F4-DP1 to form the DREAM complex that mediates global repression of cell cycle genes in G0/G1, including a subset of MMB target genes. Here, we show that overexpression of B-Myb disrupts the DREAM complex in human cells, and this activity depends on the intact MuvB-binding domain in B-Myb. Furthermore, we found that B-Myb regulates the protein expression levels of the MuvB core subunit LIN52, a key adapter for assembly of both the DREAM and MMB complexes, by a mechanism that requires S28 phosphorylation site in LIN52. Given that high expression of B-Myb correlates with global loss of repression of DREAM target genes in breast and ovarian cancer, our findings offer mechanistic insights for aggressiveness of cancers with MYBL2 amplification, and establish the rationale for targeting B-Myb to restore cell cycle control.

Farman FU, Iqbal M, Azam M, Saeed M
Nucleosomes positioning around transcriptional start site of tumor suppressor (Rbl2/p130) gene in breast cancer.
Mol Biol Rep. 2018; 45(2):185-194 [PubMed] Related Publications
Dynamic positioning of nucleosomes is pivotal in determining level of genes expression especially on or around transcription start site (TSS) of a gene. Purpose of the current study was to determine nucleosome position around TSS of Rbl2/p130. We investigated Rbl2/p130 expression in connection to nucleosome positions around its TSS among breast tumors and their adjacent normal control tissues (ANCT) using micrococcal nuclease (MNAse) digestion assay and ChIP-PCR analysis. Three fold reduced Rbl2/p130 expression in these tumor tissues were noticed compared to their control tissues. DNA obtained from MNAse digested chromatin was used as PCR template. Region between - 137 to + 140 around TSS was scanned using 3 primer pairs (P1 = - 137 to + 69; P2 = - 90 to + 69; P3 = - 33 to + 140). ~ 66% breast tumors and ~ 26% ANCT samples were positive for P1. The difference was found statistically significant (p = 0.000) with an odd ratio (OD) of 9.143, suggesting that nucleosome formation in this region is ~ 9 times more probable in tumor samples. ~ 73% of the tumor and 60% ANCT were positive for P2, which although is significant (p = 0.035) with OD = 3.250, but less preferable than P1. However, P3 was not found to be a preferred area for nucleosome occupancy (p = 0.670; OD = 1.2). Negative correlations for nucleosome positions were observed especially for P1. Our results indicate that nucleosome are present slightly downstream of TSS in routine, while in case of breast carcinogenesis nucleosomes slides 55 bases upstream of the TSS, aligning + 1 position at the center of nucleosome, hence hindering access to the transcriptional machinery.

Chudasama P, Mughal SS, Sanders MA, et al.
Integrative genomic and transcriptomic analysis of leiomyosarcoma.
Nat Commun. 2018; 9(1):144 [PubMed] Free Access to Full Article Related Publications
Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of "BRCAness", including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.

Zhu Y, Gu J, Li Y, et al.
MiR-17-5p enhances pancreatic cancer proliferation by altering cell cycle profiles via disruption of RBL2/E2F4-repressing complexes.
Cancer Lett. 2018; 412:59-68 [PubMed] Related Publications
The members of the miR-17-92 cluster are upregulated in various cancers and function as a cluster of oncogenic miRNA. Our study characterized a new function of miR-17-5p, a member of the miR-17-92 cluster, in regulating cell proliferation in pancreatic cancer. Our results indicate that miR-17-5p was up-regulated in pancreatic adenocarcinoma and directly targeted the retinoblastoma-like protein 2 (RBL2), a tumor suppressor belonging to the Rb family. High levels of miR-17-5p and low levels of RBL2 were associated with poor prognosis. RBL2 interacted with the transcription factor E2F4 and bound to the promoter regions of the E2F target genes. Disruption of the RBL2/E2F4 complex by miR-17-5p overexpression shifted the activity of E2F from gene repressing to gene activating, which induced cell cycle entry and proliferation. These results suggest that miR-17-5p promoted proliferation in pancreatic ductal adenocarcinoma cells (PDAC), and altered cell cycle profiles in vivo and in vitro, by disrupting the RBL2/E2F4-associated gene repressing complexes via direct targeting of RBL2. The new regulatory network, involving miR-17-5p and RBL2, emerges as a new target of PDAC treatment.

Hong SA, Son MW, Cho J, et al.
Low angiomotin-p130 with concomitant high Yes-associated protein 1 expression is associated with adverse prognosis of advanced gastric cancer.
APMIS. 2017; 125(11):996-1006 [PubMed] Related Publications
Angiomotin (AMOT) promotes angiogenesis and plays a role in neovascularization during tumorigenesis. Recently, the AMOT isoform, AMOT-p130, was shown to exert a regulatory effect on Yes-associated protein 1 (YAP1), a major downstream effector of the Hippo pathway. The specific roles of AMOT-p130 and YAP1 in advanced gastric cancer (AGC) are yet to be established. In this study, a total of 166 patients with AGC were enrolled, and AMOT-p130 and YAP1 levels were analyzed by immunohistochemistry using tissue microarrays. Low AMOT-p130 together with high YAP1 expression (n = 30, 18.1%) was associated with high T stage (p = 0.042), high TNM stage (p = 0.025), and venous invasion (p = 0.048). A Kaplan-Meier survival analysis with log-rank test revealed a significant correlation with decreased AMOT-p130 coupled with high nuclear YAP1 expression with shorter overall survival (p = 0.0045) and disease-free survival (p = 0.0028). Furthermore, multivariate analyses showed that the low AMOT-p130/high YAP1 expression profile was an independent prognostic factor for disease-free survival (p = 0.008, HR = 1.874, CI, 1.177-2.986) and overall survival (p = 0.012, HR = 1.903, CI, 1.152-3.143). Our findings collectively demonstrate that low AMOT-p130 combined with high YAP1 expression is correlated with an unfavorable AGC prognosis.

Li EQ, Zhang JL
Essential role of SH3GL1 in interleukin-6(IL-6)- and vascular endothelial growth factor (VEGF)-triggered p130
Hum Cell. 2017; 30(4):300-310 [PubMed] Related Publications
We recently demonstrated that interleukin-6 (IL-6)- and vascular endothelial growth factor (VEGF)-induced osteosarcoma (OS) cell proliferation and migration are parallel to significant increased expression of SH3GL1 and the phosphorylation level of P130

Liu S, Yang TB, Nan YL, et al.
Genetic variants of cell cycle pathway genes predict disease-free survival of hepatocellular carcinoma.
Cancer Med. 2017; 6(7):1512-1522 [PubMed] Free Access to Full Article Related Publications
Disruption of the cell cycle pathway has previously been related to development of human cancers. However, associations between genetic variants of cell cycle pathway genes and prognosis of hepatocellular carcinoma (HCC) remain largely unknown. In this study, we evaluated the associations between 24 potential functional single nucleotide polymorphisms (SNPs) of 16 main cell cycle pathway genes and disease-free survival (DFS) of 271 HCC patients who had undergone radical surgery resection. We identified two SNPs, i.e., SMAD3 rs11556090 A>G and RBL2 rs3929G>C, that were independently predictive of DFS in an additive genetic model with false-positive report probability (FPRP) <0.2. The SMAD3 rs11556090G allele was associated with a poorer DFS, compared with the A allele [hazard ratio (HR) = 1.46, 95% confidential interval (95% CI) = 1.13-1.89, P = 0.004]; while the RBL2 rs3929 C allele was associated with a superior DFS, compared with the G allele (HR = 0.74, 95% CI = 0.57-0.96, P = 0.023). Additionally, patients with an increasing number of unfavorable genotypes (NUGs) of these loci had a significant shorter DFS (P

Tanaka S, Suzuki K, Sakaguchi M
The prolyl oligopeptidase inhibitor SUAM-14746 attenuates the proliferation of human breast cancer cell lines in vitro.
Breast Cancer. 2017; 24(5):658-666 [PubMed] Related Publications
BACKGROUND: Prolyl oligopeptidase (POP, EC is a serine peptidase that hydrolyzes post-proline peptide bonds in peptides that are <30 amino acids in length. We previously reported that POP inhibition suppressed the growth of NB-1 human neuroblastomas cells and KATO III human gastric cancer cells. POP activity is commonly elevated in many cancers, which includes breast cancer. However, the effect of POP inhibition as a candidate breast cancer therapy is unknown.
METHODS: The effects of POP inhibition and knockdown on the proliferation of cultured human estrogen receptor-positive (ER+) MCF7 and T47D, and ER-negative (ER-) MDA-MB-231 breast cancer cell lines and the MCF12A non-tumorigenic epithelial cell line were tested by analyzing their influence on cell proliferation (WST-1 assay), cell viability (trypan blue exclusion assay), and cell cycle arrest (cell cycle analysis, cell cycle regulator proteins expression).
RESULTS: POP-specific inhibitors 3-({4-[2-(E)-styrylphenoxy]butanoyl}-L-4-hydroxyprolyl)-thiazolidine (SUAM-14746) and benzyloxycarbonyl-thiopropyl-thioprolinal and RNAi-mediated POP knockdown inhibited the proliferation of MCF7 cells without inducing cell death. SUAM-14746-induced growth inhibition was also observed in T47D and MDA-MB-231 cells, but not in MCF12A cells. This growth inhibition was associated with G
CONCLUSIONS: SUAM-14746 inhibited breast cancer cell growth in a cytostatic manner without inducing lethality, and POP-specific inhibitors may be an effective treatment against ER+ and ER- breast cancer.

Zeng H, Ortiz A, Shen PF, et al.
Angiomotin regulates prostate cancer cell proliferation by signaling through the Hippo-YAP pathway.
Oncotarget. 2017; 8(6):10145-10160 [PubMed] Free Access to Full Article Related Publications
Angiomotin (AMOT) is a family of proteins found to be a component of the apical junctional complex of vertebrate epithelial cells and is recently found to play important roles in neurofibromatosis type 2 (NF-2). Whether AMOT plays a role in prostate cancer (PCa) is unknown. AMOT is expressed as two isoforms, AMOTp80 and AMOTp130, which has a 409 aa N-terminal domain that is absent in AMOTp80. Both AMOTp80 and AMOTp130 are expressed in LNCaP and C4-2B4, but at a low to undetectable level in PC3, DU145, and BPH1 cells. Further study showed that AMOTp130 and AMOTp80 have distinct functions in PCa cells. We found that AMOTp80, but not AMOT p130, functioned as a tumor promoter by enhancing PCa cell proliferation. Mechanistic studies showed that AMOTp80 signaled through the Hippo pathway by promoting nuclear translocation of YAP, resulting in an increased expression of YAP target protein BMP4. Moreover, inhibition of BMP receptor activity by LDN-193189 abrogates AMOTp80-mediated cell proliferation. Together, this study reveals a novel mechanism whereby the AMOTp80-Merlin-MST1-LATS-YAP-BMP4 pathway leads to AMOTp80-induced tumor cell proliferation.

Lee J, Jung JH, Chae YS, et al.
Long Noncoding RNA snaR Regulates Proliferation, Migration and Invasion of Triple-negative Breast Cancer Cells.
Anticancer Res. 2016; 36(12):6289-6295 [PubMed] Related Publications
AIM: We evaluated the role of long noncoding ribonucleic acid (lncRNA) in breast cancer cell lines by quantitative reverse transcription-polymerase change reaction.
MATERIALS AND METHODS: The effects of small NF90-associated RNA (snaR) with RNA interference on proliferation, migration and invasion of MDA-MB-231 cells were observed by 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide, wound healing and transwell assay.
RESULTS: Among 90 lncRNAs, E2F transcription factor 4, p107/p130-binding (E2F4) antisense, insulin-like growth factor 2 antisense (IGF2AS), snaR, and small nucleolar RNA host gene 5 (SNHG5) were up-regulated in MDA-MB-231 and 7SK, antisense noncoding RNA in the INK4 locus (ANRIL), IGF2AS, Nespas, p53 mRNA, and snaR were up-regulated in MCF-7 cells. Down-regulation of snaR inhibited the proliferation, migration, and invasion of MDA-MD-231 breast cancer cells.
CONCLUSION: LncRNA snaR was found to be up-regulated in breast cancer cells, and the cancer progression of MDA-MB-231 cells was significantly suppressed by down-regulation of snaR. Therefore, snaR knockdown has potential as a treatment modality for triple-negative breast cancer.

Kooi IE, van Mil SE, MacPherson D, et al.
Genomic landscape of retinoblastoma in Rb
Genes Chromosomes Cancer. 2017; 56(3):231-242 [PubMed] Related Publications
Several murine retinoblastoma models have been generated by deleting the genes encoding for retinoblastoma susceptibility protein pRb and one of its family members p107 or p130. In Rb

Mushtaq M, Gaza HV, Kashuba EV
Role of the RB-Interacting Proteins in Stem Cell Biology.
Adv Cancer Res. 2016; 131:133-57 [PubMed] Related Publications
Human retinoblastoma gene RB1 is the first tumor suppressor gene (TSG) isolated by positional cloning in 1986. RB is extensively studied for its ability to regulate cell cycle by binding to E2F1 and inhibiting the transcriptional activity of the latter. In human embryonic stem cells (ESCs), only a minute trace of RB is found in complex with E2F1. Increased activity of RB triggers differentiation, cell cycle arrest, and cell death. On the other hand, inactivation of the entire RB family (RB1, RBL1, and RBL2) in human ESC induces G2/M arrest and cell death. These observations indicate that both loss and overactivity of RB could be lethal for the stemness of cells. A question arises why inactive RB is required for the survival and stemness of cells? To shed some light on this question, we analyzed the RB-binding proteins. In this review we have focused on 27 RB-binding partners that may have potential roles in different aspects of stem cell biology.

Zhao Y, Scott A, Zhang P, et al.
Regulation of paxillin-p130-PI3K-AKT signaling axis by Src and PTPRT impacts colon tumorigenesis.
Oncotarget. 2017; 8(30):48782-48793 [PubMed] Free Access to Full Article Related Publications
Protein tyrosine phosphatase receptor T (PTPRT) is frequently mutated in a variety of human cancers including colorectal cancer. Here we report that PTPRT knockout increases the size of mouse colon tumors in the Apcmin+/- genetic background, suggesting that inactivation of PTPRT promotes tumor progression. We previously demonstrated that PTPRT dephosphorylates paxillin at tyrosine-Y88 residue. Consistently, phosphorylation of Y88 paxillin (pY88) is up-regulated in colon tumors derived from Apcmin+/- Ptprt-/- mice. An important downstream effector of pY88 paxillin is the oncogene Akt. Here, we show that pY88 paxillin impacts the Akt pathway by regulating the interaction between p130cas and the p85 regulatory subunit of PI3-Kinase. Additionally, while pY88 paxillin is a substrate of the tumor suppressor phosphatase PTPRT, the corresponding kinase has not been previously identified. In this study, we demonstrate that the oncogenic kinase Src directly phosphorylates paxillin at Y88. Moreover, colorectal cancer cells that express high levels of pY88 paxillin are sensitive to dasatinib treatment, suggesting that pY88 paxillin may serve as a predictive biomarker for Src family kinase inhibitors.

Nan YL, Hu YL, Liu ZK, et al.
Relationships between cell cycle pathway gene polymorphisms and risk of hepatocellular carcinoma.
World J Gastroenterol. 2016; 22(24):5558-67 [PubMed] Free Access to Full Article Related Publications
AIM: To investigate the associiations between the polymorphisms of cell cycle pathway genes and the risk of hepatocellular carcinoma (HCC).
METHODS: We enrolled 1127 cases newly diagnosed with HCC from the Tumor Hospital of Guangxi Medical University and 1200 non-tumor patients from the First Affiliated Hospital of Guangxi Medical University. General demographic characteristics, behavioral information, and hematological indices were collected by unified questionnaires. Genomic DNA was isolated from peripheral venous blood using Phenol-Chloroform. The genotyping was performed using the Sequenom MassARRAY iPLEX genotyping method. The association between genetic polymorphisms and risk of HCC was shown by P-value and the odd ratio (OR) with 95% confidence interval (CI) using the unconditional logistic regression after adjusting for age, sex, nationality, smoking, drinking, family history of HCC, and hepatitis B virus (HBV) infection. Moreover, stratified analysis was conducted on the basis of the status of HBV infection, smoking, and alcohol drinking.
RESULTS: The HCC risk was lower in patients with the MCM4 rs2305952 CC (OR = 0.22, 95%CI: 0.08-0.63, P = 0.01) and with the CHEK1 rs515255 TC, TT, TC/TT (OR = 0.73, 95%CI: 0.56-0.96, P = 0.02; OR = 0.67, 95%CI: 0.46-0.97, P = 0.04; OR = 0.72, 95%CI: 0.56-0.92, P = 0.01, respectively). Conversely, the HCC risk was higher in patients with the KAT2B rs17006625 GG (OR = 1.64, 95%CI: 1.01-2.64, P = 0.04). In addition, the risk was markedly lower for those who were carriers of MCM4 rs2305952 CC and were also HBsAg-positive and non-drinking and non-smoking (P < 0.05, respectively) and for those who were carriers of CHEK1 rs515255 TC, TT, TC/TT and were also HBsAg-negative and non-drinking (P < 0.05, respectively). Moreover, the risk was higher for those who were carriers of KAT2B rs17006625 GG and were also HBsAg-negative (P < 0.05).
CONCLUSION: Of 12 cell cycle pathway genes, MCM4, CHEK1 and KAT2B polymorphisms may be associated with the risk of HCC.

Alessio N, Capasso S, Di Bernardo G, et al.
Mesenchymal stromal cells having inactivated RB1 survive following low irradiation and accumulate damaged DNA: Hints for side effects following radiotherapy.
Cell Cycle. 2017; 16(3):251-258 [PubMed] Free Access to Full Article Related Publications
Following radiotherapy, bone sarcomas account for a significant percentage of recurring tumors. This risk is further increased in patients with hereditary retinoblastoma that undergo radiotherapy. We analyzed the effect of low and medium dose radiation on mesenchymal stromal cells (MSCs) with inactivated RB1 gene to gain insights on the molecular mechanisms that can induce second malignant neoplasm in cancer survivors. MSC cultures contain subpopulations of mesenchymal stem cells and committed progenitors that can differentiate into mesodermal derivatives: adipocytes, chondrocytes, and osteocytes. These stem cells and committed osteoblast precursors are the cell of origin in osteosarcoma, and RB1 gene mutations have a strong role in its pathogenesis. Following 40 and 2000 mGy X-ray exposure, MSCs with inactivated RB1 do not proliferate and accumulate high levels of unrepaired DNA as detected by persistence of gamma-H2AX foci. In samples with inactivated RB1 the radiation treatment did not increase apoptosis, necrosis or senescence versus untreated cells. Following radiation, CFU analysis showed a discrete number of cells with clonogenic capacity in cultures with silenced RB1. We extended our analysis to the other members of retinoblastoma gene family: RB2/P130 and P107. Also in the MSCs with silenced RB2/P130 and P107 we detected the presence of cells with unrepaired DNA following X-ray irradiation. Cells with unrepaired DNA may represent a reservoir of cells that may undergo neoplastic transformation. Our study suggests that, following radiotherapy, cancer patients with mutations of retinoblastoma genes may be under strict controls to evaluate onset of secondary neoplasms following radiotherapy.

Hesbacher S, Pfitzer L, Wiedorfer K, et al.
RB1 is the crucial target of the Merkel cell polyomavirus Large T antigen in Merkel cell carcinoma cells.
Oncotarget. 2016; 7(22):32956-68 [PubMed] Free Access to Full Article Related Publications
The pocket protein (PP) family consists of the three members RB1, p107 and p130 all possessing tumor suppressive properties. Indeed, the PPs jointly control the G1/S transition mainly by inhibiting E2F transcription factors. Notably, several viral oncoproteins are capable of binding and inhibiting PPs. Merkel cell polyomavirus (MCPyV) is considered as etiological factor for Merkel cell carcinoma (MCC) with expression of the viral Large T antigen (LT) harboring an intact PP binding domain being required for proliferation of most MCC cells. Therefore, we analyzed the interaction of MCPyV-LT with the PPs. Co-IP experiments indicate that MCPyV-LT binds potently only to RB1. Moreover, MCPyV-LT knockdown-induced growth arrest in MCC cells can be rescued by knockdown of RB1, but not by p107 or p130 knockdown. Accordingly, cell cycle arrest and E2F target gene repression mediated by the single PPs can only in the case of RB1 be significantly reverted by MCPyV-LT expression. Moreover, data from an MCC patient indicate that loss of RB1 rendered the MCPyV-positive MCC cells LT independent. Thus, our results suggest that RB1 is the dominant tumor suppressor PP in MCC, and that inactivation of RB1 by MCPyV-LT is largely sufficient for its growth supporting function in established MCPyV-positive MCC cells.

Cross AM, Wilson AL, Guerrero MS, et al.
Breast cancer antiestrogen resistance 3-p130
Oncogene. 2016; 35(45):5850-5859 [PubMed] Free Access to Full Article Related Publications
Adhesion turnover is critical for cell motility and invasion. We previously demonstrated that the adaptor molecule breast cancer antiestrogen resistance 3 (BCAR3) promotes adhesion disassembly and breast tumor cell invasion. One of two established binding partners of BCAR3 is the adaptor molecule, p130

Fischer M, Quaas M, Nickel A, Engeland K
Indirect p53-dependent transcriptional repression of Survivin, CDC25C, and PLK1 genes requires the cyclin-dependent kinase inhibitor p21/CDKN1A and CDE/CHR promoter sites binding the DREAM complex.
Oncotarget. 2015; 6(39):41402-17 [PubMed] Free Access to Full Article Related Publications
The transcription factor p53 is central to cell cycle control by downregulation of cell cycle-promoting genes upon cell stress such as DNA damage. Survivin (BIRC5), CDC25C, and PLK1 encode important cell cycle regulators that are repressed following p53 activation. Here, we provide evidence that p53-dependent repression of these genes requires activation of p21 (CDKN1A, WAF1, CIP1). Chromatin immunoprecipitation (ChIP) data indicate that promoter binding of B-MYB switches to binding of E2F4 and p130 resulting in a replacement of the MMB (Myb-MuvB) by the DREAM complex. We demonstrate that this replacement depends on p21. Furthermore, transcriptional repression by p53 requires intact DREAM binding sites in the target promoters. The CDE and CHR cell cycle promoter elements are the sites for DREAM binding. These elements as well as the p53 response of Survivin, CDC25C, and PLK1 are evolutionarily conserved. No binding of p53 to these genes is detected by ChIP and mutation of proposed p53 binding sites does not alter the p53 response. Thus, a mechanism for direct p53-dependent transcriptional repression is not supported by the data. In contrast, repression by DREAM is consistent with most previous findings and unifies models based on p21-, E2F4-, p130-, and CDE/CHR-dependent repression by p53. In conclusion, the presented data suggest that the p53-p21-DREAM-CDE/CHR pathway regulates p53-dependent repression of Survivin, CDC25C, and PLK1.

Mileo AM, Mattarocci S, Matarrese P, et al.
Hepatitis C virus core protein modulates pRb2/p130 expression in human hepatocellular carcinoma cell lines through promoter methylation.
J Exp Clin Cancer Res. 2015; 34:140 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Hepatitis C Virus (HCV) infection is associated with chronically evolving disease and development of hepatocellular carcinoma (HCC), albeit the mechanism of HCC induction by HCV is still controversial. The nucleocapsid (core) protein of HCV has been shown to be directly implicated in cellular transformation and immortalization, enhancing the effect of oncogenes and decreasing the one of tumor suppressor genes, as RB1 and its protein product pRB. With the aim of identifying novel molecular mechanisms of hepatocyte transformation by HCV, we examined the effect of HCV core protein on the expression of the whole Retinoblastoma (RB) family of tumor and growth suppressor factors, i.e. pRb, p107 and pRb2/p130.
METHODS: We used a model system consisting of the HuH-7, HCV-free, human hepatocellular carcinoma cell line and of the HuH-7-CORE cells derived from the former and constitutively expressing the HCV core protein. We determined pRb, p107 and pRb2/p130 protein and mRNA amount of the respective genes RB1, RBL1 and RBL2, RBL2 promoter activity and methylation as well as DNA methyltransferase 1 (DNMT1) and 3b (DNMT3b) expression level. The effect of pRb2/p130 over-expression on the HCV core-expressing HuH-7-CORE cells was also evaluated.
RESULTS: We found that the HCV core protein expression down-regulated pRb2/p130 protein and mRNA levels in HuH-7-CORE cells by inducing promoter hyper-methylation with the concomitant up-regulation of DNMT1 and DNMT3b expression. When pRb2/p130 expression was artificially re-established in HuH-7-CORE cells, cell cycle analysis outlined an accumulation in the G0/G1 phase, as expected.
CONCLUSIONS: HCV core appears indeed able to significantly down-regulate the expression and the function of two out of three RB family tumor and growth suppressor factors, i.e. pRb and pRb2/p130. The functional consequences at the level of cell cycle regulation, and possibly of more complex cell homeostatic processes, may represent a plausible molecular mechanism involved in liver transformation by HCV.

Meng WJ, Pathak S, Ding ZY, et al.
Special AT-rich sequence binding protein 1 expression correlates with response to preoperative radiotherapy and clinical outcome in rectal cancer.
Cancer Biol Ther. 2015; 16(12):1738-45 [PubMed] Free Access to Full Article Related Publications
Our recent study showed the important role of special AT-rich sequence binding protein 1 (SATB1) in the progression of human rectal cancer. However, the value of SATB1 in response to radiotherapy (RT) for rectal cancer hasn't been reported so far. Here, SATB1 was determined using immunohistochemistry in normal mucosa, biopsy, primary cancer, and lymph node metastasis from 132 rectal cancer patients: 66 with and 66 without preoperative RT before surgery. The effect of SATB1 knockdown on radiosensitivity was assessed by proliferation-based assay and clonogenic assay. The results showed that SATB1 increased from normal mucosa to primary cancer, whereas it decreased from primary cancer to metastasis in non-RT patients. SATB1 decreased in primary cancers after RT. In RT patients, positive SATB1 was independently associated with decreased response to preoperative RT, early time to metastasis, and worse survival. SATB1 negatively correlated with ataxia telangiectasia mutated (ATM) and pRb2/p130, and positively with Ki-67 and Survivin in RT patients, and their potential interaction through different canonical pathways was identified in network ideogram. Taken together, our findings disclose for the first time that radiation decreases SATB1 expression and sensitizes cancer cells to confer clinical benefit of patients, suggesting that SATB1 is predictive of response to preoperative RT and clinical outcome in rectal cancer.

Ullah F, Khan T, Ali N, et al.
Promoter Methylation Status Modulate the Expression of Tumor Suppressor (RbL2/p130) Gene in Breast Cancer.
PLoS One. 2015; 10(8):e0134687 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant expression of tumor suppressor genes may correspond to the abnormal cell development and tumorigenesis. Rbl2/p130, a member of retinoblastoma family of proteins, has growth suppressive properties. Numerous studies reported de-regulation of Rbl2/p130 in various types of cancer as a consequence of a number of genetic alterations. However, role of epigenetic mechanisms like DNA methylation in Rbl2/p130 expression remains elusive.
METHODS: In the current study, 76 breast cancer tumors along with normal tissues (n = 76), blood (n = 76) of respective individuals and control blood (n = 50) were analyzed. Rbl2/p130 expression was analyzed by quantitative real time PCR (syber green method). Promoter methylation status was studied through methylation specific PCR of bisulfite converted genomic DNA. Data was analyzed using various statistical tests.
RESULTS: We report significantly reduced Rbl2/p130 expression (P = 0.001) in tumors tissues as compared to control samples. Similarly, Rbl2/p130 expression varies with age and disease stages (P = 0.022), which suggest its involvement in tumor progression. Aberrant promoter methylation (Δmeth) was found in almost all the diseased samples and that was significantly different (P<0.001) with control samples. Similarly, methylation status varies significantly with tumor progression stages (P = 0.022). Hyper-methylation was observed at -1, +3, +15 and +75 of Rbl2/p130 promoter flanking around the TSS. Statistical analysis revealed that Rbl2/p130 expression negatively correlates to its promoter methylation (r = -0.412) in tumor tissues. Our results reflect an epigenetic regulation of Rbl2/p130 expression in breast cancer. This highlights the importance of Rbl2/p130 promoter methylation in breast cancer pathogenesis.

Cai L, Ye Y, Jiang Q, et al.
Epstein-Barr virus-encoded microRNA BART1 induces tumour metastasis by regulating PTEN-dependent pathways in nasopharyngeal carcinoma.
Nat Commun. 2015; 6:7353 [PubMed] Free Access to Full Article Related Publications
Epstein-Barr virus (EBV), aetiologically linked to nasopharyngeal carcinoma (NPC), is the first human virus found to encode many miRNAs. However, how these viral miRNAs precisely regulate the tumour metastasis in NPC remains obscure. Here we report that EBV-miR-BART1 is highly expressed in NPC and closely associated with pathological and advanced clinical stages of NPC. Alteration of EBV-miR-BART1 expression results in an increase in migration and invasion of NPC cells in vitro and causes tumour metastasis in vivo. Mechanistically, EBV-miR-BART1 directly targets the cellular tumour suppressor PTEN. Reduction of PTEN dosage by EBV-miR-BART1 activates PTEN-dependent pathways including PI3K-Akt, FAK-p130(Cas) and Shc-MAPK/ERK1/2 signalling, drives EMT, and consequently increases migration, invasion and metastasis of NPC cells. Reconstitution of PTEN rescues all phenotypes generated by EBV-miR-BART1, highlighting the role of PTEN in EBV-miR-BART-driven metastasis in NPC. Our findings provide new insights into the metastasis of NPC regulated by EBV and advocate for developing clinical intervention strategies against NPC.

Kumbrink J, Soni S, Laumbacher B, et al.
Identification of Novel Crk-associated Substrate (p130Cas) Variants with Functionally Distinct Focal Adhesion Kinase Binding Activities.
J Biol Chem. 2015; 290(19):12247-55 [PubMed] Free Access to Full Article Related Publications
Elevated levels of p130(Cas) (Crk-associated substrate)/BCAR1 (breast cancer antiestrogen resistance 1 gene) are associated with aggressiveness of breast tumors. Following phosphorylation of its substrate domain, p130(Cas) promotes the integration of protein complexes involved in multiple signaling pathways and mediates cell proliferation, adhesion, and migration. In addition to the known BCAR1-1A (wild-type) and 1C variants, we identified four novel BCAR1 mRNA variants, generated by alternative first exon usage (1B, 1B1, 1D, and 1E). Exons 1A and 1C encode for four amino acids (aa), whereas 1D and 1E encode for 22 aa and 1B1 encodes for 50 aa. Exon 1B is non-coding, resulting in a truncated p130(Cas) protein (Cas1B). BCAR1-1A, 1B1, and variant 1C mRNAs were ubiquitously expressed in cell lines and a survey of human tissues, whereas 1B, 1D, and 1E expression was more restricted. Reconstitution of all isoforms except for 1B in p130(Cas)-deficient murine fibroblasts induced lamellipodia formation and membrane ruffling, which was unrelated to the substrate domain phosphorylation status. The longer isoforms exhibited increased binding to focal adhesion kinase (FAK), a molecule important for migration and adhesion. The shorter 1B isoform exhibited diminished FAK binding activity and significantly reduced migration and invasion. In contrast, the longest variant 1B1 established the most efficient FAK binding and greatly enhanced migration. Our results indicate that the p130(Cas) exon 1 variants display altered functional properties. The truncated variant 1B and the longer isoform 1B1 may contribute to the diverse effects of p130(Cas) on cell biology and therefore will be the target of future studies.

Chung YJ, Kim HJ, Park SH, et al.
Transcriptome analysis reveals that Müllerian inhibiting substance regulates signaling pathways that contribute to endometrial carcinogenesis.
Int J Oncol. 2015; 46(5):2039-46 [PubMed] Related Publications
Müllerian inhibiting substance (MIS) has been shown to inhibit growth of a number of tumors in vitro and/or in vivo, but the downstream pathways which it regulates are not fully understood. In the present study we show that MIS type II receptor was highly expressed in AN3CA cells, a cell line derived from human endometrial cancer cell in which MIS-treatment caused a reduction of cell viability, and induced cellular apoptosis and genes involved cell cycle arrest. To understand the genome-wide effects of MIS on gene regulation, we performed serial gene expression analyses from 0 to 96 h at 24 h intervals after treating AN3CA cells with MIS. Transcriptomic analysis of molecular changes induced by MIS identified 2,688 differentially expressed genes that were significantly up- or down-regulated during the 96 h study period. When the 2,688 differentially expressed genes were mapped to known biological processes, Wnt-, cancer-, proteolysis-, cytoskeleton-, cell cycle-, apoptosis-, and MAPK-signaling pathways emerged as the functions most significantly changed by MIS in AN3CA cells. Furthermore, western blot analysis validated that protein expression of cell cycle inhibitory genes, apoptotic protease activating factor-1 (APAF-1), β-catenin-interacting protein (ICAT), Rb related protein 130 (p130), and inhibitor of disheveled Dvl and Axin complex (IDAX), were gradually increased over the time of the study, whereas downstream cell cycle activating genes, cyclin-dependent kinase 2 (CDK2) and phospho-c-Jun were downregulated in MIS-treated AN3CA cells. These transcriptome analyses support previous observations that MIS functions as a tumor suppressor, potentially by regulating signaling pathways that could contribute to endometrial carcinogenesis, and indicating that MIS should be considered as a potential treatment for endometrial cancer.

Schwentner R, Papamarkou T, Kauer MO, et al.
EWS-FLI1 employs an E2F switch to drive target gene expression.
Nucleic Acids Res. 2015; 43(5):2780-9 [PubMed] Free Access to Full Article Related Publications
Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.

Vilas JM, Ferreirós A, Carneiro C, et al.
Transcriptional regulation of Sox2 by the retinoblastoma family of pocket proteins.
Oncotarget. 2015; 6(5):2992-3002 [PubMed] Free Access to Full Article Related Publications
Cellular reprogramming to iPSCs has uncovered unsuspected links between tumor suppressors and pluripotency factors. Using this system, it was possible to identify tumor suppressor p27 as a repressor of Sox2 during differentiation. This led to the demonstration that defects in the repression of Sox2 can contribute to tumor development. The members of the retinoblastoma family of pocket proteins, pRb, p107 and p130, are negative regulators of the cell cycle with tumor suppressor activity and with roles in differentiation. In this work we studied the relative contribution of the retinoblastoma family members to the regulation of Sox2 expression. We found that deletion of Rb or p130 leads to impaired repression of Sox2, a deffect amplified by inactivation of p53. We also identified binding of pRb and p130 to an enhancer with crucial regulatory activity on Sox2 expression. Using cellular reprogramming we tested the impact of the defective repression of Sox2 and confirmed that Rb deficiency allows the generation of iPSCs in the absence of exogenous Sox2. Finally, partial depletion of Sox2 positive cells reduced the pituitary tumor development initiated by Rb loss in vivo. In summary, our results show that Sox2 repression by pRb is a relevant mechanism of tumor suppression.

Rashid NN, Yusof R, Watson RJ
A B-myb--DREAM complex is not critical to regulate the G2/M genes in HPV-transformed cell lines.
Anticancer Res. 2014; 34(11):6557-63 [PubMed] Related Publications
BACKGROUND/AIM: It is well-established that HPV E7 proteins, encoded by human papillomavirus (HPV) genes, frequently associated with cervical cancers bind avidly to the retinoblastoma (RB) family of pocket proteins and disrupt their association with members of the E2F transcription factor family. Our previous study showed that the repressive p130-dimerization partner, RB-like, E2F and multi-vulval class (DREAM) complex was disrupted by HPV16 E7 proteins in order to maintain the viral replication in CaSki cells. However, we would like to address whether the activator B-myb-DREAM complex is critical in regulating the replication and mitosis phase since our previous study showed increased B-myb-DREAM expression in HPV-transformed cell lines when compared to control cells.
RESULTS: The association of B-myb with both LIN-54 and LIN-9 was equally decreased by depleting LIN-54 in CaSki cells. Flow cytometry analysis showed that LIN-54 depletion caused an increased proportion of G2/M cells in T98G, SiHa and CaSki cells. The mRNA levels of certain S/G2 genes such as cyclin B, aurora kinase A and Polo-like kinase 1 have demonstrated a marginal increased in CaSki-Lin-54-depleted cells when compared to SiHa- and T98G-Lin-54-depleted cells. We further confirmed this experiment by depleting the B-myb itself in CaSki cells and the results showed the same pattern of cell cycle and mRNA levels for S/G2 genes when compared to LIN-54- and LIN-9-depleted cells.
CONCLUSION: The B-myb-DREAM complex might not be vital for progression through mitosis in cells lacking a G1/S checkpoint and not as crucial as the p130-DREAM complex for the survival of the HPV virus.

Xu XL, Singh HP, Wang L, et al.
Rb suppresses human cone-precursor-derived retinoblastoma tumours.
Nature. 2014; 514(7522):385-8 [PubMed] Free Access to Full Article Related Publications
Retinoblastoma is a childhood retinal tumour that initiates in response to biallelic RB1 inactivation and loss of functional retinoblastoma (Rb) protein. Although Rb has diverse tumour-suppressor functions and is inactivated in many cancers, germline RB1 mutations predispose to retinoblastoma far more strongly than to other malignancies. This tropism suggests that retinal cell-type-specific circuitry sensitizes to Rb loss, yet the nature of the circuitry and the cell type in which it operates have been unclear. Here we show that post-mitotic human cone precursors are uniquely sensitive to Rb depletion. Rb knockdown induced cone precursor proliferation in prospectively isolated populations and in intact retina. Proliferation followed the induction of E2F-regulated genes, and depended on factors having strong expression in maturing cone precursors and crucial roles in retinoblastoma cell proliferation, including MYCN and MDM2. Proliferation of Rb-depleted cones and retinoblastoma cells also depended on the Rb-related protein p107, SKP2, and a p27 downregulation associated with cone precursor maturation. Moreover, Rb-depleted cone precursors formed tumours in orthotopic xenografts with histological features and protein expression typical of human retinoblastoma. These findings provide a compelling molecular rationale for a cone precursor origin of retinoblastoma. More generally, they demonstrate that cell-type-specific circuitry can collaborate with an initiating oncogenic mutation to enable tumorigenesis.

Further References

Raschellà G, Tanno B, Bonetto F, et al.
The RB-related gene Rb2/p130 in neuroblastoma differentiation and in B-myb promoter down-regulation.
Cell Death Differ. 1998; 5(5):401-7 [PubMed] Related Publications
The retinoblastoma family of nuclear factors is composed of RB, the prototype of the tumour suppressor genes and of the strictly related genes p107 and Rb2/p130. The three genes code for proteins, namely pRb, p107 and pRb2/p130, that share similar structures and functions. These proteins are expressed, often simultaneously, in many cell types and are involved in the regulation of proliferation and differentiation. We determined the expression and the phosphorylation of the RB family gene products during the DMSO-induced differentiation of the N1E-115 murine neuroblastoma cells. In this system, pRb2/p130 was strongly up-regulated during mid-late differentiation stages, while, on the contrary, pRb and p107 resulted markedly decreased at late stages. Differentiating N1E-115 cells also showed a progressive decrease in B-myb levels, a proliferation-related protein whose constitutive expression inhibits neuronal differentiation. Transfection of each of the RB family genes in these cells was able, at different degrees, to induce neuronal differentiation, to inhibit [3H]thymidine incorporation and to down-regulate the activity of the B-myb promoter.

Raschellà G, Tanno B, Bonetto F, et al.
Retinoblastoma-related protein pRb2/p130 and its binding to the B-myb promoter increase during human neuroblastoma differentiation.
J Cell Biochem. 1997; 67(3):297-303 [PubMed] Related Publications
Neuroblastoma cells can undergo neural differentiation upon treatment with a variety of chemical inducers and growth factors. During this process, many cell cycle-related genes are downregulated while differentiation-specific genes are triggered. The retinoblastoma family proteins, pRb, p107, and pRb2/p130, are involved in transcriptional repression of proliferation genes, mainly through their interaction with the E2F transcription factors. We report that pRb2/p130 expression levels increased during differentiation of neuroblastoma cell line LAN-5. On the other hand, both pRb and p107 decreased and underwent progressive dephosphorylation at late differentiation times. The expression of B-myb and c-myb, two targets of the retinoblastoma family proteins, were downregulated in association with the increase of pRb2/p130, which was detected as the major component of the complex with E2F on the E2F site of the B-myb promoter in differentiated cells. Interestingly, E2F4, a preferential partner of p107 and pRb2/p130, was upregulated and underwent changes in cellular localization during differentiation. In conclusion, our data suggest a major role of pRb2/p130 in the regulation of B-myb promoter during neural differentiation despite the importance of cofactors in modulating the function of the retinoblastoma family proteins.

Minimo C, Bibbo M, Claudio PP, et al.
The role of pRb2/p130 protein in diagnosing lung carcinoma on fine needle aspiration biopsies.
Pathol Res Pract. 1999; 195(2):67-70 [PubMed] Related Publications
The retinoblastoma gene family is composed of three members: the retinoblastoma gene, one of the most studied tumor suppressor genes, and two related genes: p107 and pRb2/p130. These proteins are also known as the pocket proteins due to a unique structural and functional domain composed of subdomains A and B separated by a spacer region that is highly conserved among each of the proteins. These proteins exhibit unique growth suppressive properties that are cell type specific, suggesting that although the pocket proteins may complement each other, they are not fully functionally redundant. With the development of antibodies recognizing these three proteins it is now possible to detect expression in formalin-embedded specimens. Recent studies on 235 lung cancers, using immunohistochemical techniques, suggested an independent role for Rb2/p130 in the development and/or progression of human lung carcinoma. We found a statistically significant inverse relationship between the histological grading (degree of malignant potential) and the expression of pRb/p105, p107 and pRb2/p130 in squamous cell carcinomas, meaning that an increase in grading resulted in a significant decrease in protein expression. This phenomenon was particularly evident for pRb2/p130 (p < .0001) which had the highest percentage of undetectable levels in all the specimens examined and the tightest inverse correlation (p value) with both the histological grading and PCNA expression in the most aggressive tumor types, suggesting an important role for pRb2/p130 in the pathogenesis and progression of certain lung cancers. We further explored the expression of pRb2/p130 protein in routine archival FNAB cytological material from 30 Patients with lung cancer using immunocytochemical techniques, comparing protein expression with tumor type. Two pathologists evaluated the staining pattern and scored the percentage of positive cells. Of the 30 neoplasms, 27 displayed a positive staining for pRb2/p130. In particular, we detected pRb2/p130 in 9 (100%) squamous carcinomas, 11 (84%) adenocarcinomas, 5 (100%) BAC, and 2 (66%) SCC. The percentage of positive nuclei varied in different tumors with the highest expression level in adenocarcinomas. Immunocytochemistry represents a sensitive method for detection of pRb2/p130 expression in cytological or archival specimens, and the level of detection seems to be comparable to paraffin sections. Therefore, this methodology could be used in the preoperative evaluation of routine cytological specimens in order to improve the diagnostic and prognostic evaluation of lung cancer patients.

Baldi A, Esposito V, De Luca A, et al.
Differential expression of Rb2/p130 and p107 in normal human tissues and in primary lung cancer.
Clin Cancer Res. 1997; 3(10):1691-7 [PubMed] Related Publications
Two proteins, p107 and pRb2/p130, which are structurally and functionally similar to the product of the retinoblastoma gene (pRb), were cloned by taking advantage of their ability to bind transforming proteins of DNA tumor viruses through a particular region called the "pocket domain." Like pRb, both proteins play a fundamental role in growth control. Using immunocytochemical techniques, we examined a variety of normal human tissues for the expression of pRb2/p130 and p107. Both proteins were expressed ubiquitously, although a different tissue distribution and/or level of expression were found in various organs. Terminally differentiated cells, such as neurons and skeletal muscle, showed high expression levels for Rb2/p130, whereas p107 was expressed at higher levels in other cell types such as epithelia of the breast and prostate. We then examined the expression pattern of Rb2/p130 in 158 specimens of human lung cancer and found an inverse correlation between the histological grading of the tumors, the development of metastasis, and the level of expression of Rb2/p130.

Helin K, Holm K, Niebuhr A, et al.
Loss of the retinoblastoma protein-related p130 protein in small cell lung carcinoma.
Proc Natl Acad Sci U S A. 1997; 94(13):6933-8 [PubMed] Free Access to Full Article Related Publications
The retinoblastoma gene family consists of the tumor suppressor protein pRB and its two relatives p107 and p130. These proteins have been implicated in the regulation of cell cycle progression, in part, through inactivation of members of the E2F transcription factor family. Overexpression of pRB, p107, or p130 leads to growth arrest in the G1 phase of the cell cycle, and this arrest is abolished by complex formation with the adenovirus E1A, human papilloma virus E7, or simian virus 40 T oncoproteins. Inactivation of pRB by gross structural alterations or point mutations in the RB-1 gene has been described in a variety of human tumors, including retinoblastomas, osteosarcomas, and small cell lung carcinomas. Despite the structural and functional similarity between pRB, p107, and p130, alterations in the latter two proteins have not been identified in human tumors. We have screened a panel of 17 small cell lung carcinoma cell lines for the presence of functional p107 and p130 by evaluating their ability to form complexes with E1A in vitro. In the GLC2 small cell lung carcinoma cells no p130 protein was detected. The loss of the p130 protein is the result of a single point mutation within a splice acceptor sequence in the GLC2 genomic DNA. This mutation eliminates exon 2, leading to an in-frame stop codon, and no detectable protein is produced. These data are, to our knowledge, the first to describe the loss of p130 as a consequence of a genetic alteration, suggesting that not only pRB but also the other members of the family may contribute to tumorigenesis, providing a rationale for the observation that the DNA tumor viruses selectively target all the members of the retinoblastoma protein family.

Susini T, Baldi F, Howard CM, et al.
Expression of the retinoblastoma-related gene Rb2/p130 correlates with clinical outcome in endometrial cancer.
J Clin Oncol. 1998; 16(3):1085-93 [PubMed] Related Publications
PURPOSE: The retinoblastoma gene is the prototype of tumor-suppressor genes and has been shown to be involved in the pathogenesis and progression of several human malignancies. In this study, we determined the relation between the expression of a newly discovered retinoblastoma-related gene Rb2/p130 and outcome in patients with endometrial carcinoma.
PATIENTS AND METHODS: pRb2/p130 expression was determined immunohistochemically in specimens of endometrial carcinoma (stages I to IV) from 100 patients who underwent surgery as the first treatment. The pRb2/p130 status was analyzed in relation to the length of disease-free survival and disease-specific survival.
RESULTS: Decreased levels of pRb2/p130 in endometrial cancer cells was significantly associated with a decreased probability of remaining disease-free after treatment (P = .003) and with decreased probability of survival (P < .0001). In a multivariate analysis, pRb2/p130 status (P = .004), tumor stage (P = .009), and ploidy status (P = .02) were independent predictors of clinical outcome. The risk of dying of disease was increased substantially (risk ratio, 4.91; 95% confidence interval, 1.66 to 14.54) among patients with decreased levels of pRb2/p130 in tumor cells.
CONCLUSION: In patients with endometrial carcinoma who did not receive radiotherapy or chemotherapy before surgery, the presence of decreased levels of pRb2/p130 in tumor cells is associated with a significantly increased risk of recurrence and death of disease, independent of tumor stage and ploidy status.

Massaro-Giordano M, Baldi G, De Luca A, et al.
Differential expression of the retinoblastoma gene family members in choroidal melanoma: prognostic significance.
Clin Cancer Res. 1999; 5(6):1455-8 [PubMed] Related Publications
We evaluated 55 samples of choroidal melanoma managed by enucleation. Knowing that the immunohistochemical expression of the retinoblastoma gene family members Rb/p105, p107, and pRb2/p130 was inversely correlated with the degree of malignancy in at least some histological types, we investigated the expression of these three proteins in choroidal melanoma. We focused on the relationship between patient survival and the immunohistochemical detection of the retinoblastoma proteins. No correlation with clinical outcome was found for Rb/p105 and p107. However, we found pRb2/p130 to be an independent prognostic factor correlating positively or directly with patient survival times and indirectly or inversely with the degree of malignancy. Demonstration of the prognostic value of the immunohistochemical expression of pRb2/p130 is of significance, even if additional studies are required to confirm these data and to compare the prognostic value of pRb2/p130 immunodetection to that of other recently proposed markers, such as p53.

Claudio PP, Howard CM, Fu Y, et al.
Mutations in the retinoblastoma-related gene RB2/p130 in primary nasopharyngeal carcinoma.
Cancer Res. 2000; 60(1):8-12 [PubMed] Related Publications
Nasopharyngeal carcinoma (NPC) is an endemic cancer in southern China and northern Africa, and its pathogenesis is not yet well defined at the molecular level. Although the involvement of p53 and of the retinoblastoma gene (RB/p105) in NPC has been well studied, there is paucity of mutational data regarding the retinoblastoma-related gene RB2/p130 in primary tumors and particularly in NPC. We have shown previously that RB2/p130 could be rearranged in a nasopharyngeal cell line. In the present study, we screened by single-strand conformation polymorphism and sequence analysis the retinoblastoma-related gene RB2/p130 for mutations within exons 19-22. Mutations in the RB2/p130 gene were detected in 3 of 10 primary human NPCs from Northern Africa (30%). These findings, along with previous data showing that genetic replacement of RB2/p130 restores a normal growth pathway in the nasopharyngeal cell line Hone-1, strengthen the hypothesis that genetic changes of RB2/p130 may be involved in the development and/or progression of nasopharyngeal cancer and suggest that RB2/p130 could be considered a tumor suppressor gene and may be a candidate for novel gene therapeutic approaches for NPC.

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