ABI1

Gene Summary

Gene:ABI1; abl-interactor 1
Aliases: E3B1, ABI-1, ABLBP4, NAP1BP, SSH3BP, SSH3BP1
Location:10p11.2
Summary:This gene encodes a member of the Abelson-interactor family of adaptor proteins. These proteins facilitate signal transduction as components of several multiprotein complexes, and regulate actin polymerization and cytoskeletal remodeling through interactions with Abelson tyrosine kinases. The encoded protein plays a role in macropinocytosis as a component of the WAVE2 complex, and also forms a complex with EPS8 and SOS1 that mediates signal transduction from Ras to Rac. This gene may play a role in the progression of several malignancies including melanoma, colon cancer and breast cancer, and a t(10;11) chromosomal translocation involving this gene and the MLL gene has been associated with acute myeloid leukemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 14. [provided by RefSeq, Sep 2011]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Protein:abl interactor 1
HPRD
Source:NCBIAccessed: 27 February, 2015

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 27 February 2015 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.

  • Cell Movement
  • Chromosome 10
  • Base Sequence
  • Mutation
  • Young Adult
  • Cancer Gene Expression Regulation
  • Neoplasm Metastasis
  • Signal Transducing Adaptor Proteins
  • Translocation
  • Infant
  • MLL
  • Transcription Factors
  • ABI1
  • Down-Regulation
  • Immunohistochemistry
  • Leukaemia
  • src Homology Domains
  • Up-Regulation
  • Fusion Proteins, bcr-abl
  • Leukemic Gene Expression Regulation
  • KMT2A
  • Messenger RNA
  • Cell Adhesion
  • DNA-Binding Proteins
  • Chromosome 11
  • Neoplastic Cell Transformation
  • Chronic Myelogenous Leukemia
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • Homeodomain Proteins
  • Phosphorylation
  • ras Proteins
  • Molecular Sequence Data
  • Vascular Cell Adhesion Molecule-1
  • Binding Sites
  • Protein Isoforms
  • Adenocarcinoma
  • Proto-Oncogenes
  • Proteasome Endopeptidase Complex
  • Neoplasm Proteins
  • Oncogene Fusion Proteins
Tag cloud generated 27 February, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (1)

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: ABI1 (cancer-related)

Steinestel K, Brüderlein S, Lennerz JK, et al.
Expression and Y435-phosphorylation of Abelson interactor 1 (Abi1) promotes tumour cell adhesion, extracellular matrix degradation and invasion by colorectal carcinoma cells.
Mol Cancer. 2014; 13:145 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The Abelson tyrosine kinase (c-Abl) inhibitor STI571 (Glivec®) has been shown to effectively inhibit colorectal cancer cell migration and invasion. The c-Abl substrate abelson interactor 1 (Abi1) is a key regulator of actin reorganization and upregulated in colorectal carcinoma. The specific role of Abi1 in relation to extracellular matrix degradation and effects of targeting Abi1 phosphorylation have not yet been examined. Here, we investigated the role of Abi1 in relation to invasive properties in colorectal cancer.
METHODS AND RESULTS: In 56 primary human colorectal carcinoma samples, we found overexpression of Abi1 in 39% at the invasive edge of the tumour, associated with an infiltrative phenotype and high-grade tumour cell budding (p = 0.001). To explore the role of Abi1 in vitro, we employed the Abi1 expressing and KRAS-mutated CHD1 model and performed matrix degradation assays that showed Abi1 localization at specific sites of matrix degradation. Moreover, quantification of matrix dissolution demonstrated suppression after RNAi knockdown of Abi1 by 95% (p = 0.001). Importantly, treatment with STI571 did abolish Abi1 Y435-phosphorylation, suppressed the matrix dissolution, decreased fibronectin attachment, and suppressed cell invasion through reconstituted extracellular matrix.
CONCLUSION: Our data indicate that phosphorylated Abi1 contributes to the invasive properties of colorectal cancer.

Chorzalska A, Salloum I, Shafqat H, et al.
Low expression of Abelson interactor-1 is linked to acquired drug resistance in Bcr-Abl-induced leukemia.
Leukemia. 2014; 28(11):2165-77 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The basis for persistence of leukemic stem cells in the bone marrow microenvironment remains poorly understood. We present evidence that signaling cross-talk between α4 integrin and Abelson interactor-1 (Abi-1) is involved in the acquisition of an anchorage-dependent phenotype and drug resistance in Bcr-Abl-positive leukemia cells. Comparison of Abi-1 (ABI-1) and α4 integrin (ITGA4) gene expression in relapsing Bcr-Abl-positive CD34+progenitor cells demonstrated a reduction in Abi-1 and an increase in α4 integrin mRNA in the absence of Bcr-Abl mutations. This inverse correlation between Abi-1 and α4 integrin expression, as well as linkage to elevated phospho-Akt and phospho-Erk signaling, was confirmed in imatinib mesylate -resistant leukemic cells. These results indicate that the α4-Abi-1 signaling pathway may mediate acquisition of the drug-resistant phenotype of leukemic cells.

Bhat HF, Baba RA, Adams ME, Khanday FA
Role of SNTA1 in Rac1 activation, modulation of ROS generation, and migratory potential of human breast cancer cells.
Br J Cancer. 2014; 110(3):706-14 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
BACKGROUND: Alpha-1-syntrophin (SNTA1) has been implicated in the activation of Rac1. However, the underlying mechanism has not yet been explored. Here, we show that a novel complex, involving SNTA1, P66shc, and Grb2 proteins, is involved in Rac1 activation.
METHODS: Co-immunoprecipitation assays were used to show the complex formation, while siRNAs and shRNAs were used to downregulate expression of these proteins. Various Rac1 activation assays and functional assays, such as migration assays, in vitro wound healing assays, cell proliferation assays, and ROS generation assays, were also performed.
RESULTS: The results showed a significant increase in activation of Rac1 when SNTA1 and P66shc were overexpressed, whereas depletion of SNTA1 and P66shc expression effectively reduced the levels of active Rac1. The results indicated a significant displacement of Sos1 protein from Grb2 when SNTA1 and P66shc are overexpressed in breast cancer cell lines, resulting in Sos1 predominantly forming a complex with Eps8 and E3b1. In addition, the SNTA1/P66shc-mediated Rac1 activation resulted in an increase in reactive oxygen species (ROS) production and migratory potential in human breast cancer cells.
CONCLUSION: Together, our results present a possible mechanism of Rac1 activation involving SNTA1 and emphasise its role in ROS generation, cell migration, and acquisition of malignancy.

Steinestel K, Gläsle F, Brüderlein S, et al.
[Abelson interactor 1 (Abi1) in colorectal cancer. From synaptic plasticity to tumor cell migration].
Pathologe. 2013; 34 Suppl 2:189-94 [PubMed] Related Publications
BACKGROUND: Invasion and metastatic dissemination of tumor cells defines the prognosis of patients with colorectal cancer (CRC). The Abelson interactor 1 (Abi1), a 65 kD substrate of the eponymous Abelson tyrosine kinase, interacts with phosphatidylinositol-3-kinase (PI3K) and heterogeneous nuclear ribonucleoprotein K (hnRNP K) and is a key regulator of cytoskeletal reorganization during synaptic maturation and cellular migration.
AIM: The aim of this study was the analysis of Abi1 expression patterns and to elucidate the role in cytoskeletal reorganization in colorectal carcinoma cells.
MATERIAL AND METHODS: The methods used in this study were immunohistochemistry; immunofluorescence microscopy; liposomal transfection and protein analysis by Western blotting.
RESULTS: The results showed that Abi1 is expressed at the invasive front of colorectal carcinomas and localizes to the leading edge of lamellipodia in cultured colorectal carcinoma cells. A phosphorylated isoform of Abi1 that stains positively in these microcompartments disappears after treatment with the tyrosine kinase inhibitor STI571 (Glivec®). The RNA interference (RNAi) approach knockdown of Abi1 as well as treatment with STI571 induce a shift in cellular morphology from broad lamellipodia-like to thin filopodia-like cellular protrusions.
DISCUSSION: The initial results support a central role for phosphorylated Abi1 in the formation of lamellipodia-like cellular protrusions as a prerequisite for cellular migration of colorectal carcinoma cells. As phosphorylation of Abi1 could be pharmaceutically targeted with STI571, this indicates a possible therapeutic option to prevent the gain of a metastatic phenotype in colorectal cancer. This possibility will be further evaluated in ongoing research.

Baba RA, Bhat HF, Wani LA, et al.
E3B1/ABI-1 isoforms are down-regulated in cancers of human gastrointestinal tract.
Dis Markers. 2012; 32(4):273-9 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The expression of E3B1/ABI-1 protein and its role in cancer progression and prognosis are largely unknown in the majority of solid tumors. In this study, we examined the expression pattern of E3B1/ABI-1 protein in histologically confirmed cases of esophageal (squamous cell carcinoma and adenocarcinoma), gastro-esophageal junction, colorectal cancers and corresponding normal tissues freshly resected from a cohort of 135 patients, by Western Blotting and Immunofluorescence Staining. The protein is present in its phosphorylated form in cells and tissues. Depending on the extent of phosphorylation it is either present in hyper-phosphorylated (M. Wt. 72 kDa) form or in hypo-phosphorylated form (M. Wt. 68 kDa and 65 kDa). A thorough analysis revealed that expression of E3B1/ABI-1 protein is significantly decreased in esophageal, gastro-esophageal junction and colorectal carcinomas irrespective of age, gender, dietary and smoking habits of the patients. The decrease in expression of E3B1/ABI-1 was consistently observed for all the three isoforms. However, the decrease in the expression of isoforms varied with different forms of cancers. Down-regulation of E3B1/ABI-1 expression in human carcinomas may play a critical role in tumor progression and in determining disease prognosis.

Wang C, Tran-Thanh D, Moreno JC, et al.
Expression of Abl interactor 1 and its prognostic significance in breast cancer: a tissue-array-based investigation.
Breast Cancer Res Treat. 2011; 129(2):373-86 [PubMed] Related Publications
Abl interactor 1 (Abi1) is an adaptor protein involved in cell migration. Previous in vitro work suggested that Abi1 is a regulator of breast cancer proliferation, migration, and invasion. In the present study, we explore the expression of Abi1 and its downstream effector phospho-Akt (p-Akt) in a series of breast cancers and correlate their expression with clinicopathological and survival data. Using tissue microarrays, 988 patients with invasive breast carcinoma were evaluated by immunohistochemistry. Statistical correlation was performed to determine associations between Abi1 and p-Akt expression and standard breast clinicopathological factors. The prognostic value of Abi1 and p-Akt for disease-free (DFS) and overall survival (OS) was also evaluated. Abi1 expression was demonstrated in 33.7% (314/933) of invasive carcinomas, while p-Akt was expressed in 46.7% (441/944). There was a significant association between Abi1 and p-Akt expression (P=0.001). Abi1 expression showed significant positive correlation with older age at diagnosis and the Ki67 index. Most importantly, it was demonstrated to be an independent predictor of both DFS and OS (HR = 1.6 and 1.5, P<0.001, respectively). There was no association between p-Akt expression and survival. To the best of our knowledge, this is the first study evaluating Abi1 expression in a large group of breast cancers. Our analysis demonstrated that tumors expressing high levels of Abi1 are significantly associated with early recurrence and worse survival on multivariate analysis. This suggests that Abi1 expression has potential as a molecular marker to refine outcome prediction in breast cancer patients.

Cui MH, Yu WD, Dong JQ, Liu YL
[Effect of Abl-interacting protein 1 overexpression upon human gastric cancer cell proliferation in vitro].
Zhonghua Yi Xue Za Zhi. 2009; 89(44):3111-5 [PubMed] Related Publications
OBJECTIVE: To investigate the expression of Abl-interacting protein 1 (ABI1) in normal gastric mucosal cell line GES-1 and gastric cancer cell line AGS, and the effects of ABI1 gene overexpression upon the proliferation of human gastric cancer cell AGS in vitro.
METHODS: Firstly the ABI1 expression in GES-1 and AGS cells were identified by immunohistochemistry, immunofluorescence, RT-PCR, real-time PCR and Western blot. Secondly human gastric cancer cell line AGS was cultured and transfected with recombinant MSCV-GFP-ABI1 plasmid or blank plasmid MSCV-GPF. Real-time PCR and Western blot were used to detect the mRNA and protein expression of ABI1. And lastly the cell proliferation was detected by CCK-8 assay.
RESULTS: ABI1 was expressed both in normal gastric mucosal cell line GES-1 and in gastric cancer cell line AGS. Compared to GES-1 cells, the ABI1 expression in AGS cells was lowered significantly. There were no significant differences in the ABI1 mRNA and protein expression between the AGS and AGS-MSCV-GFP groups. Compared to those of the AGS group, the ABI1 mRNA expression levels of the AGS-MSCV-GFP-ABI1 group increased by 1.87 times (P = 0.002). The protein expression levels of the AGS-MSCV-GFP-ABI1 group were remarkably higher than those of the AGS and AGS-MSCV-GFP groups (P = 0.002). CCK-8 assay showed that there were no significant differences in the proliferation rates at different time points between the AGS and AGS-MSCV-GFP groups. However, the proliferation rates at the time points of 24, 48, 72 and 96 hours of the AGS-MSCV-GFP-ABI1 were 1.46 +/- 0.31, 4.75 +/- 0.12, 6.62 +/- 0.32 and 8.96 +/- 0.27 respectively. And they were significantly lower than the proliferation rates of the AGS and AGS-MSCV-GFP groups (P < 0.01).
CONCLUSION: ABI1 gene is down-regulated in gastric cancer cells. The ABI1 overexpression effectively inhibits the proliferation in human gastric cancer cell lines. It suggests that ABI1 may be involved in gastric cancer pathogenesis by regulating the proliferation of gastric carcinomas cells.

Nahar R, Müschen M
Pre-B cell receptor signaling in acute lymphoblastic leukemia.
Cell Cycle. 2009; 8(23):3874-7 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
B cell lineage ALL represents by far the most frequent malignancy in children and is also common in adults. Despite significant advances over the past four decades, cytotoxic treatment strategies have recently reached a plateau with cure rates at 80 percent for children and 55 percent for adults. Relapse after cytotoxic drug treatment, initial drug-resistance and dose-limiting toxicity are among the most frequent complications of current therapy approaches. For this reason, pathway-specific treatment strategies in addition to cytotoxic drug treatment seem promising to further improve therapy options for ALL patients. In a recent study on 111 cases of pre-B cell-derived human ALL, we found that ALL cells carrying a BCR-ABL1-gene rearrangement lack expression of a functional pre-B cell receptor in virtually all cases. In a proof-of-principle experiment, we studied pre-B cell receptor function during progressive leukemic transformation of pre-B cells in BCR-ABL1-transgenic mice: Interestingly, signaling from the pre-B cell receptor and the oncogenic BCR-ABL1 kinase are mutually exclusive and only "crippled" pre-B cells that fail to express a functional pre-B cell receptor are permissive to transformation by BCR-ABL1.

Sun X, Li C, Zhuang C, et al.
Abl interactor 1 regulates Src-Id1-matrix metalloproteinase 9 axis and is required for invadopodia formation, extracellular matrix degradation and tumor growth of human breast cancer cells.
Carcinogenesis. 2009; 30(12):2109-16 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Abl interactor 1 (Abi1) is a key regulator of actin polymerization/depolymerization. The involvement of Abi1 in the development of abnormal cytoskeletal functions of cancer cells has recently been reported. It remains unclear, however, how Abi1 exerts its effects in tumor cells and whether it contributes to tumor progression in vivo. We report here a novel function for Abi1 in the regulation of invadopodia formation and Src-inhibitor of differentiation protein 1 (Id1)-matrix metalloproteinase (MMP)-9 pathway in MDA-MB-231 human breast cancer cells. Abi1 is found in the invadopodia of MDA-MB-231 cells. Epigenetic silencing of the Abi1 gene by short hairpin RNA in MDA-MB-231 cells impaired the formation of invadopodia and resulted in downregulation of the Src activation and Id1/MMP-9 expression. The decreased invadopodia formation and MMP-9 expression correlate with a reduction in the ability of these cells to degrade extracellular matrix. Remarkably, the knockdown of Abi1 expression inhibited tumor cell proliferation and migration in vitro and slowed tumor growth in vivo. Taken together, these results indicate that the Abi1 signaling plays a critical role in breast cancer progression and suggest that this pathway may serve as a therapeutic target for the treatment of human breast cancer.

Yu W, Sun X, Clough N, et al.
Abi1 gene silencing by short hairpin RNA impairs Bcr-Abl-induced cell adhesion and migration in vitro and leukemogenesis in vivo.
Carcinogenesis. 2008; 29(9):1717-24 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Abl interactor (Abi) 1 was first identified as the downstream target of Abl tyrosine kinases and was found to be dysregulated in leukemic cells expressing oncogenic Bcr-Abl and v-Abl. Although the accumulating evidence supports a role of Abi1 in actin cytoskeleton remodeling and growth factor/receptor signaling, it is not clear how it contributes to Bcr-Abl-induced leukemogenesis. We show here that Abi1 gene silencing by short hairpin RNA attenuated the Bcr-Abl-induced abnormal actin remodeling, membrane-type 1 metalloproteinase clustering and inhibited cell adhesion and migration on fibronectin-coated surfaces. Although the knock down of Abi1 expression did not affect growth factor-independent growth of Bcr-Abl-transformed Ba/F3 cells in vitro, it impeded competitive expansion of these cells in non obese diabetic (NOD)/ severe combined immuno-deficiency (SCID) mice. Remarkably, the knock down of Abi1 expression in Bcr-Abl-transformed Ba/F3 cells impaired the leukemogenic potential of these cells in NOD/SCID mice. Abi1 contributes to Bcr-Abl-induced leukemogenesis in part through Src family kinases, as the knock down of Abi1 expression attenuates Bcr-Abl-stimulated activation of Lyn. Together, these data provide for the first time the direct evidence that supports a critical role of Abi1 pathway in the pathogenesis of Bcr-Abl-induced leukemia.

Gupta M, Milani L, Hermansson M, et al.
Expression of BCR-ABL1 oncogene relative to ABL1 gene changes overtime in chronic myeloid leukemia.
Biochem Biophys Res Commun. 2008; 366(3):848-51 [PubMed] Related Publications
Using a quantitative single nucleotide polymorphism (SNP) assay we have investigated the changes in the expression of the BCR-ABL1 oncogene relative to the wild-type ABL1 and BCR alleles in cells from chronic myeloid leukemia (CML) patients not responding to therapy. The results show a progressive increase in the BCR-ABL1 oncogene expression at the expense of decreased expression of the ABL1 allele, not involved in the fusion. No relative changes in the expression of the two BCR alleles were found. These results demonstrate that allele-specific changes in gene expression, with selective, progressive silencing of the wild-type ABL1 allele in favor of the oncogenic BCR-ABL1 allele occur in CML patients with therapy-resistant disease.

Jenei V, Jakus J
[The role of EGF receptor-dependent e3B1/Abi1 protein as a tumor suppressor protein in malignant tumors].
Orv Hetil. 2005; 146(24):1293-9 [PubMed] Related Publications
Hungary is among the leading countries in Europe regarding the mortality and incidence of different types of tumours. Therefore, developing effective therapies is especially important in this country. Investigation of tumour formation and progression on the molecular level is required to develop possible therapeutical targets. Such targets can be proteins with tumour suppressor function, which inhibit intracellular signalling processes that under pathophysiological conditions can lead to uncontrolled cell proliferation and tumour formation. Protein e3B1/Abi-1, which belongs to the family of Abl-interactors, was isolated recently as a possible tumour suppressor. As a partner of Abl kinase, its role has been investigated in the development and progression of some types of leukemias, however, more and more experimental data suggest that it is a general suppressor protein. According to the latest results, e3B1/Abi-1 via the Ras small G-protein has an essential role in the regulation of cell proliferation, and via Rac activation it can affect actin remodelling, cell adhesion and migration. Cell proliferation is important in tumour development, while cell adhesion and migration has a role in metastasis formation. The latest results showed deletion of the gene encoding protein e3B1/Abi-1 in prostate cancer, loss of its expression during the progression of some types of leukemias, and there are data on the effect of imatinib mesylate (Gleevec or outside USA Glivec, Novartis), one of the newest drugs in leukemia treatment, on the phosphorylation of e3B1/Abi-1 as well. This report summarizes the data published on protein e3B1/Abi-1, with special interest in practical implications.

Watahiki A, Waki K, Hayatsu N, et al.
Libraries enriched for alternatively spliced exons reveal splicing patterns in melanocytes and melanomas.
Nat Methods. 2004; 1(3):233-9 [PubMed] Related Publications
It is becoming increasingly clear that alternative splicing enables the complex development and homeostasis of higher organisms. To gain a better understanding of how splicing contributes to regulatory pathways, we have developed an alternative splicing library approach for the identification of alternatively spliced exons and their flanking regions by alternative splicing sequence enriched tags sequencing. Here, we have applied our approach to mouse melan-c melanocyte and B16-F10Y melanoma cell lines, in which 5,401 genes were found to be alternatively spliced. These genes include those encoding important regulatory factors such as cyclin D2, Ilk, MAPK12, MAPK14, RAB4, melastatin 1 and previously unidentified splicing events for 436 genes. Real-time PCR further identified cell line-specific exons for Tmc6, Abi1, Sorbs1, Ndel1 and Snx16. Thus, the ASL approach proved effective in identifying splicing events, which suggest that alternative splicing is important in melanoma development.

Funato Y, Terabayashi T, Suenaga N, et al.
IRSp53/Eps8 complex is important for positive regulation of Rac and cancer cell motility/invasiveness.
Cancer Res. 2004; 64(15):5237-44 [PubMed] Related Publications
IRSp53 has been characterized as an adaptor protein that links Rho-family small GTPases, such as Rac, to reorganization of the actin cytoskeleton. Here, we search for other binding partners for the IRSp53 SH3 domain and identify Eps8 as the major binding protein in fibroblasts and various cancer cell lines. Eps8 has been shown to form a Rac-specific guanine nucleotide exchange factor complex with Abi-1 and Sos-1, which seems essential for ruffling formation induced by oncogenic Ras. We confirm the IRSp53/Eps8 complex formation in vivo and the direct association between Eps8 NH(2)-terminal proline-rich sequence and IRSp53 SH3 domain. This complex synergistically activates Rac by reinforcing the formation of the Eps8/Abi-1/Sos-1 Rac-guanine nucleotide exchange factor complex, which mediates positive regulation of Rac activity. In addition, IRSp53/Eps8 complex formation as determined by fluorescent resonance energy transfer analysis, occurs at the leading edge of motile cells, and the motility and invasiveness of HT1080 fibrosarcoma cells are suppressed by inhibiting complex formation. These findings implicate the importance of the IRSp53/Eps8 complex in Rac activation and metastatic behavior of the malignant tumor cells.

Morerio C, Rosanda C, Rapella A, et al.
Is t(10;11)(p11.2;q23) involving MLL and ABI-1 genes associated with congenital acute monocytic leukemia?
Cancer Genet Cytogenet. 2002; 139(1):57-9 [PubMed] Related Publications
Congenital, or perinatal, leukemias are rarely observed, but retrospective molecular studies seem to suggest a more frequent onset in prenatal life. Myelocytic types are common, and chromosome band 11q23 rearrangements at the MLL locus are characteristic genetic markers. The fusion of the MLL gene with one of its partners, ABI-1, has recently been described in two infant leukemia patients with monocytic involvement and good clinical outcome. We report a case of congenital monocytic leukemia with the same gene involvement and good response to chemotherapy. The blast metaphases were probed by fluorescence in situ hybridization, and t(10;11)(p11.2;q23) involving MLL and ABI-1 genes was demonstrated with the same breakpoint in ABI-1. The congenital presentation of this case suggests a possible relationship of this genetic event with in utero leukemogenesis.

Yao R, Wang Y, Lubet RA, You M
Differentially expressed genes associated with mouse lung tumor progression.
Oncogene. 2002; 21(37):5814-21 [PubMed] Related Publications
To detect altered gene expression associated with mouse lung tumor progression, we compared the gene expression profile of lung adenocarcinomas with that of lung adenomas and normal lungs. Autoradiographic analysis showed that among the 588 genes surveyed, 152 genes were detected and the remaining 436 genes did not give any signals. A gene-specific semiquantitative reverse transcription polymerase chain reaction method was used to confirm the expression profile. A total of 29 genes was found to be differentially expressed in mouse lung tumors when compared to normal lungs. The pattern of expression, either underexpression or overexpression, was the same for 10 genes between adenocarcinomas and adenomas. Among them, seven genes were overexpressed, two genes were underexpressed and one gene was lost. Interestingly, 19 genes showed differential expression or increased incidence or difference in level of change between lung adenomas and adenocarcinomas, including Stat1, ADAP, IGFBP-6, PDGF-A, TGF-beta2, Int-3, VEGFR2, BAX, BAG-1, c-Jun, FasL, TRAIL, YB-1, CD31, Cdc42, B-raf, Rab-2, Abi-1, and ACE. These genes can be designated as candidate 'lung tumor progression' (LTP) genes because their expression changes may specifically affect lung tumor progression in mice. Further analyses of these candidate LTP genes may provide new leads for elucidation of lung tumor progression in mice.

Ikeguchi A, Yang HY, Gao G, Goff SP
Inhibition of v-Abl transformation in 3T3 cells overexpressing different forms of the Abelson interactor protein Abi-1.
Oncogene. 2001; 20(36):4926-34 [PubMed] Related Publications
The abi-1 gene encodes a protein that binds and is phosphorylated by the Abelson protein tyrosine kinase. Constructs expressing a full-length abi-1 cDNA, and a smaller cDNA arising from an alternatively spliced form, were generated and tested for their effect on transformation of NIH3T3 cells by the Abelson murine leukemia virus. Overexpression of both forms of the protein strongly inhibited transformation by the wild-type P160 strain of the virus, but not by the non-interacting mutant P90A strain. The inhibition required the SH3 domain of Abi-1, suggesting that a direct interaction was required for the effect. Rare breakthrough P160 transformants of the Abi-1 overexpressing lines were found to have downregulated Abi-1 protein levels by a post-transcriptional mechanism.

Shibuya N, Taki T, Mugishima H, et al.
t(10;11)-acute leukemias with MLL-AF10 and MLL-ABI1 chimeric transcripts: specific expression patterns of ABI1 gene in leukemia and solid tumor cell lines.
Genes Chromosomes Cancer. 2001; 32(1):1-10 [PubMed] Related Publications
The recurrent translocation t(10;11) is associated with acute myeloid leukemia (AML). The AF10 gene on chromosome 10 at band p12 and MLL at 11q23 fuse in the t(10;11)(p12;q23). Recently, we have identified ABI1 as a new partner gene for MLL in an AML patient with a t(10;11)(p11.2;q23). The ABI1 is a human homologue of the mouse Abl-interactor 1 (Abi1), encoding an Abl-binding protein. The ABI1 protein exhibits sequence similarity to homeotic genes, and contains several polyproline stretches and a src homology 3 (SH3) domain. To clarify the clinical features of t(10;11)-leukemias, we investigated 6 samples from acute leukemia patients with t(10;11) and MLL rearrangement and detected MLL-AF10 chimeric transcripts in 5 samples and MLL-ABI1 in one. The patient with MLL-ABI1 chimeric transcript is the second case described, thus confirming that the fusion of the MLL and ABI1 genes is a recurring abnormality. Both of the patients with MLL-ABI1 chimeric transcript are surviving, suggesting that these patients have a better prognosis than the patients with MLL-AF10. To investigate the roles of AF10 and ABI1 further, we examined the expression of these genes in various cell lines and fresh tumor samples using the reverse transcriptase-polymerase chain reaction method. Although AF10 was expressed in almost all cell lines similarly, the expression patterns of ABI1 were different between leukemia and solid tumor cell lines, suggesting the distinctive role of each isoform of ABI1 in these cell lines. We also determined the complete mouse Abi1 sequence and found that the sequence matched with human ABI1 better than the originally reported Abi1 sequence. Further functional analysis of the MLL-AF10 and MLL-ABI1 fusion proteins will provide new insights into the leukemogenesis of t(10;11)-AML.

Macoska JA, Xu J, Ziemnicka D, et al.
Loss of expression of human spectrin src homology domain binding protein 1 is associated with 10p loss in human prostatic adenocarcinoma.
Neoplasia. 2001 Mar-Apr; 3(2):99-104 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
The gene encoding human spectrin Src homology domain binding protein 1, or Hssh3bp1, which is a marker of macropinocytic vesicles and a potential regulator of macropinocytosis, co-localizes to a YAC containing chromosome 10p sequences at loci D10S89 and D10S111 that are frequently deleted in prostate tumors. Expression of Hssh3bp1 was evaluated at the protein level in 17 paired normal and malignant prostate tumor samples using the monoclonal antibody 2G8 to Hssh3bp1. These experiments demonstrated that 4/6 tumors (67%) with 10p deletion failed to express Hssh3bp1 protein compared to 5/11 (46%) tumors with intact 10p. Thus, loss of Hssh3bp1 expression is concordant with allelic loss of adjacent 10p sequences in human prostate tumors. In addition, two prostate tumor cell lines contain an exon skipping mutation in the Hssh3bp1 gene that leads to the abnormal splicing of the mRNA and loss of a portion of Abl tyrosine kinase SH3 domain binding site in the protein. These data are consistent with a role for Hssh3bp1 as a candidate tumor suppressor gene inactivated during prostate tumorigenesis.

So CW, So CK, Cheung N, et al.
The interaction between EEN and Abi-1, two MLL fusion partners, and synaptojanin and dynamin: implications for leukaemogenesis.
Leukemia. 2000; 14(4):594-601 [PubMed] Related Publications
The mixed lineage leukaemia gene, MLL (also called HRX, ALL-1) in acute leukaemia is fused to at least 16 identified partner genes that display diverse structural and biochemical properties. Using GST pull down and the yeast two hybrid system, we show that two different MLL fusion partners with SH3 domains, EEN and Abi-1, interact with dynamin and synaptojanin, both of which are involved in endocytosis. Synaptojanin, a member of the inositol phosphatase family that has recently been shown to regulate cell proliferation and survival, is also known to bind to Eps15, the mouse homologue of AF1p, another fusion partner of MLL. Expression studies show that synaptojanin is strongly expressed in bone marrow and immature leukaemic cell lines, very weakly in peripheral blood leukocytes and absent in Raji, a mature B cell line. We found that the SH3 domains of EEN and Abi-1 interact with different proline-rich domains of synaptojanin while the EH domains of Eps15 interact with the NPF motifs of synaptojanin. In vitro competitive binding assays demonstrate that EEN displays stronger binding affinity than Abi-1 and may compete with it for synaptojanin. These findings suggest a potential link between MLL fusion-mediated leukaemogenesis and the inositol-signalling pathway.

Taki T, Shibuya N, Taniwaki M, et al.
ABI-1, a human homolog to mouse Abl-interactor 1, fuses the MLL gene in acute myeloid leukemia with t(10;11)(p11.2;q23).
Blood. 1998; 92(4):1125-30 [PubMed] Related Publications
Recurrent translocation t(10;11) has been reported to be associated with acute myeloid leukemia (AML). Recently, two types of chimeric transcripts, MLL-AF10 in t(10;11)(p12;q23) and CALM-AF10 in t(10;11)(p13;q14), were isolated. t(10;11) is strongly associated with complex translocations, including invins(10;11) and inv(11)t(10;11), because the direction of transcription of AF10 is telomere to centromere. We analyzed a patient of AML with t(10;11)(p11.2;q23) and identified ABI-1 on chromosome 10p11.2, a human homolog to mouse Abl-interactor 1 (Abi-1), fused with MLL. Whereas the ABI-1 gene bears no homology with the partner genes of MLL previously described, the ABI-1 protein exhibits sequence similarity to protein of homeotic genes, contains several polyproline stretches, and includes a src homology 3 (SH3) domain at the C-terminus that is required for binding to Abl proteins in mouse Abi-1 protein. Recently, e3B1, an eps8 SH3 binding protein 1, was also isolated as a human homolog to mouse Abi-1. Three types of transcripts of ABI-1 gene were expressed in normal peripheral blood. Although e3B1 was considered to be a full-length ABI-1, the MLL-ABI-1 fusion transcript in this patient was formed by an alternatively spliced ABI-1. Others have shown that mouse Abi-1 suppresses v-ABL transforming activity and that e3B1, full-length ABI-1, regulates cell growth. In-frame MLL-ABI-1 fusion transcripts combine the MLL AT-hook motifs and DNA methyltransferase homology region with the homeodomain homologous region, polyproline stretches, and SH3 domain of alternatively spliced transcript of ABI-1. Our results suggest that the ABI-1 gene plays a role in leukemogenesis by translocating to MLL.

Dai Z, Quackenbush RC, Courtney KD, et al.
Oncogenic Abl and Src tyrosine kinases elicit the ubiquitin-dependent degradation of target proteins through a Ras-independent pathway.
Genes Dev. 1998; 12(10):1415-24 [PubMed] Article available free on PMC after 01/05/2015 Related Publications
Oncogenic forms of the Abl and Src tyrosine kinases trigger the destruction of the Abi proteins, a family of Abl-interacting proteins that antagonize the oncogenic potential of Abl after overexpression in fibroblasts. The destruction of the Abi proteins requires tyrosine kinase activity and is dependent on the ubiquitin-proteasome pathway. We show that degradation of the Abi proteins occurs through a Ras-independent pathway. Significantly, expression of the Abi proteins is lost in cell lines and bone marrow cells isolated from patients with aggressive Bcr-Abl-positive leukemias. These findings suggest that loss of Abi proteins may be a component in the progression of Bcr-Abl-positive leukemias and identify a novel pathway linking activated nonreceptor protein tyrosine kinases to the destruction of specific target proteins through the ubiquitin-proteasome pathway.

Shi Y, Alin K, Goff SP
Abl-interactor-1, a novel SH3 protein binding to the carboxy-terminal portion of the Abl protein, suppresses v-abl transforming activity.
Genes Dev. 1995; 9(21):2583-97 [PubMed] Related Publications
A novel cellular protein, Abl-interactor-1 (Abi-1), which specifically interacts with the carboxy-terminal region of Abl oncoproteins, has been identified in a mouse leukemia cell line. The protein exhibits sequence similarity to homeotic genes, contains several polyproline stretches, and includes a src homology 3 (SH3) domain at its very carboxyl terminus that is required for binding to Abl proteins. The abi-1 gene has been mapped to mouse chromosome 2 and is genetically closely linked to the c-abl locus. The gene is widely expressed in the mouse, with highest levels of mRNA found in the bone marrow, spleen, brain, and testes. The Abi-1 protein coimmunoprecipitates with v-Abl and serves as a substrate for kinase activity. When overexpressed in NIH-3T3 cells, abi-1 potently suppresses the transforming activity of Abelson leukemia virus expressing the full-length p160v-abl kinase but does not affect the transforming activity of viruses expressing a truncated p90v-abl or v-src kinases. We suggest that the Abi-1 protein may serve as a regulator of Abl function in transformation or in signal transduction.

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