ITCH

Gene Summary

Gene:ITCH; itchy E3 ubiquitin protein ligase
Aliases: AIF4, AIP4, ADMFD, NAPP1
Location:20q11.22
Summary:This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein plays a role in multiple cellular processes including erythroid and lymphoid cell differentiation and the regulation of immune responses. Mutations in this gene are a cause of syndromic multisystem autoimmune disease. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:E3 ubiquitin-protein ligase Itchy homolog
Source:NCBIAccessed: 20 August, 2015

Ontology:

What does this gene/protein do?
Show (35)
Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 20 August 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.

  • Protein Binding
  • Mast Cells
  • Apoptosis
  • Childhood Cancer
  • Proto-Oncogene Proteins c-kit
  • Adolescents
  • Skin
  • Multiple Endocrine Neoplasia
  • Western Blotting
  • Viral Proteins
  • Survival Rate
  • Repressor Proteins
  • Spleen
  • Signal Transduction
  • Mastocytosis, Systemic
  • Skin Diseases, Metabolic
  • Proto-Oncogene Proteins
  • Mutation
  • Chromosome 20
  • Mastocytosis, Cutaneous
  • Antineoplastic Agents
  • Melanoma
  • Multiple Primary Neoplasms
  • Ubiquitin-Protein Ligases
  • HeLa Cells
  • Cancer Gene Expression Regulation
  • DNA-Binding Proteins
  • Skin Diseases
  • Ubiquitins
  • Neoplastic Cell Transformation
  • Pruritus
  • Skin Cancer
  • Gene Expression Profiling
  • Differential Diagnosis
  • Pedigree
  • Infant
  • Neurofibromatosis 1
  • Tumor Suppressor Proteins
  • RTPCR
  • Cancer DNA
Tag cloud generated 20 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (4)

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: ITCH (cancer-related)

Yardley DA, Weaver R, Melisko ME, et al.
EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-Expressing Breast Cancer.
J Clin Oncol. 2015; 33(14):1609-19 [PubMed] Related Publications
PURPOSE: Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression.
PATIENTS AND METHODS: Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigator's choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3).
RESULTS: Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC.
CONCLUSION: Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

Abu-Odeh M, Salah Z, Herbel C, et al.
WWOX, the common fragile site FRA16D gene product, regulates ATM activation and the DNA damage response.
Proc Natl Acad Sci U S A. 2014; 111(44):E4716-25 [PubMed] Free Access to Full Article Related Publications
Genomic instability is a hallmark of cancer. The WW domain-containing oxidoreductase (WWOX) is a tumor suppressor spanning the common chromosomal fragile site FRA16D. Here, we report a direct role of WWOX in DNA damage response (DDR) and DNA repair. We show that Wwox deficiency results in reduced activation of the ataxia telangiectasia-mutated (ATM) checkpoint kinase, inefficient induction and maintenance of γ-H2AX foci, and impaired DNA repair. Mechanistically, we show that, upon DNA damage, WWOX accumulates in the cell nucleus, where it interacts with ATM and enhances its activation. Nuclear accumulation of WWOX is regulated by its K63-linked ubiquitination at lysine residue 274, which is mediated by the E3 ubiquitin ligase ITCH. These findings identify a novel role for the tumor suppressor WWOX and show that loss of WWOX expression may drive genomic instability and provide an advantage for clonal expansion of neoplastic cells.

Abedini MR, Wang PW, Huang YF, et al.
Cell fate regulation by gelsolin in human gynecologic cancers.
Proc Natl Acad Sci U S A. 2014; 111(40):14442-7 [PubMed] Free Access to Full Article Related Publications
Chemoresistance is a major hurdle in cancer treatment. Down-regulation of apoptosis pathways is one of the key determinants for chemoresistance. Here, we report higher gelsolin (GSN) levels in chemoresistant gynecological cancer cells compared with their sensitive counterparts. cis-Diammine dichloroplatinium (II) (CDDP)-induced GSN down-regulation is associated with its cleavage and apoptosis. Although the C-terminal GSN fragment (C-GSN) sensitized chemoresistant cells to CDDP, intact GSN and its N-terminal fragment (N-GSN) attenuated this response. GSN silencing also facilitated CDDP-induced apoptosis in chemoresistant cells. In contrast, intact GSN (I-GSN) was prosurvival in the presence of CDDP through a FLICE-like inhibitory protein (FLIP)-Itch interaction. This interaction was colocalized in the perinuclear region that could be dissociated by CDDP in sensitive cells, thereby inducing FLIP ubiquitination and degradation, followed by apoptosis. In resistant cells, GSN was highly expressed and CDDP failed to abolish the I-GSN-FLIP-Itch interaction, resulting in the dysregulation of the downstream responses. In addition, we investigated the association between GSN expression in ovarian serous adenocarcinoma and progression free survival and overall survival, as well as clinical prognosis. GSN overexpression was significantly associated with more aggressive behavior and more cancer deaths and supported our hypothesis that high GSN expression confers chemoresistance in cancer cells by altering the GSN-FLIP-Itch interaction. These findings are in agreement with the notion that GSN plays an important role in the regulation of gynecological cell fate as reflected in dysregulation in chemosensitivity.

Vilarinho S, Erson-Omay EZ, Harmanci AS, et al.
Paediatric hepatocellular carcinoma due to somatic CTNNB1 and NFE2L2 mutations in the setting of inherited bi-allelic ABCB11 mutations.
J Hepatol. 2014; 61(5):1178-83 [PubMed] Related Publications
Hepatocellular carcinoma (HCC) rarely occurs in childhood. We describe a patient with new onset of pruritus at 8 months of age who at 17 months of age was found to have a 2.5 cm HCC. To delineate the possible genetic basis of this tumour, we performed whole exome sequencing (WES) of the germline DNA and identified two novel predictably deleterious missense mutations in ABCB11, encoding bile salt export pump (BSEP), confirmed in the parental DNA as bi-allelic and inherited. Although inherited ABCB11 mutations have previously been linked to HCC in a small number of cases, the molecular mechanisms of hepatocellular carcinogenesis in ABCB11 disease are unknown. WES of the HCC tissue uncovered somatic driver mutations in the beta-catenin (CTNNB1) and nuclear-factor-erythroid-2-related-factor-2 (NFE2L2) genes. Moreover, clonality analysis predicted that the CTNNB1 mutation was clonal and occurred earlier during carcinogenesis, whereas the NFE2L2 mutation was acquired later. Interestingly, background liver parenchyma showed no inflammation or fibrosis and BSEP expression was preserved. This is the first study to identify somatic CTNNB1 and NFE2L2 mutations in early childhood arisen in the setting of inherited bi-allelic ABCB11 mutations. Rapid WES analysis expedited this child's diagnosis and treatment, and likely improved her prognosis.

Cox JL, Wilder PJ, Wuebben EL, et al.
Context-dependent function of the deubiquitinating enzyme USP9X in pancreatic ductal adenocarcinoma.
Cancer Biol Ther. 2014; 15(8):1042-52 [PubMed] Free Access to Full Article Related Publications
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadly malignancies. Recently, the deubiquitinating protease USP9X has been shown to behave as an oncogene in a number of neoplasms, including those of breast, brain, colon, esophagus and lung, as well as KRAS wild-type PDAC. However, other studies suggest that USP9X may function as a tumor-suppressor in a murine PDAC model when USP9X expression is depleted during early pancreatic development. To address the conflicting findings surrounding the role of USP9X in PDAC, we examined the effects of knocking down USP9X in five human PDAC cell lines (BxPC3, Capan1, CD18, Hs766T, and S2-013). We demonstrate that knocking down USP9X in each of the PDAC cell lines reduces their anchorage-dependent growth. Using an inducible shRNA system to knock down USP9X in both BxPC3 and Capan1 cells, we also determined that USP9X is necessary for the anchorage-independent growth. In addition, knockdown of USP9X alters the cell cycle profile of BxPC3 cells and increases their invasive capacity. Finally, we show that an inhibitor of deubiquitinating proteases, WP1130, induces significant cytotoxicity in each of the five PDAC cell lines tested. Overall, our work and the work of others indicate that the function and role of USP9X is highly context-dependent. Although USP9X may function as a tumor-suppressor during the establishment of PDAC, data presented here argue that USP9X promotes cell growth in advanced PDAC cells when PDAC is typically diagnosed. Hence, USP9X may be a promising therapeutic target for the treatment of advanced PDAC.

Miyagaki T, Sugaya M
Immunological milieu in mycosis fungoides and Sézary syndrome.
J Dermatol. 2014; 41(1):11-8 [PubMed] Related Publications
Tumor genesis and development are driven by a combination of intrinsic events such as oncogene activation and tumor-suppressor gene inactivation, and extrinsic events that are dependent on the interaction with the stroma. Different types of growth factors, cytokines and chemokines secreted by the surrounding stromal cells are thought to play key roles in solid tumor progression. Accumulating evidence indicates that the immunological milieu plays an essential role in tumor development, not only in solid tumors, but also in hematopoietic malignancies. Understanding the interactions between tumor cells and microenvironment in mycosis fungoides (MF) and Sézary syndrome (SS) could provide a basis for the development of new treatments for these diseases that are sometimes resistant to current therapies. This article focuses on the wide variety of cell types and immunological milieus, affecting the characteristic features of MF and SS, such as skin-homing of tumor cells, T-helper type 2-dominant tumor microenvironment, accumulation of dermal dendritic cells, epidermal hyperplasia, angiogenesis and pruritus.

Mascarenhas Cdo C, Ferreira da Cunha A, Brugnerotto AF, et al.
Identification of target genes using gene expression profile of granulocytes from patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors.
Leuk Lymphoma. 2014; 55(8):1861-9 [PubMed] Related Publications
Differential gene expression analysis by suppression subtractive hybridization with correlation to the metabolic pathways involved in chronic myeloid leukemia (CML) may provide a new insight into the pathogenesis of CML. Among the overexpressed genes found in CML at diagnosis are SEPT5, RUNX1, MIER1, KPNA6 and FLT3, while PAN3, TOB1 and ITCH were decreased when compared to healthy volunteers. Some genes were identified and involved in CML for the first time, including TOB1, which showed a low expression in patients with CML during tyrosine kinase inhibitor treatment with no complete cytogenetic response. In agreement, reduced expression of TOB1 was also observed in resistant patients with CML compared to responsive patients. This might be related to the deregulation of apoptosis and the signaling pathway leading to resistance. Most of the identified genes were related to the regulation of nuclear factor κB (NF-κB), AKT, interferon and interleukin-4 (IL-4) in healthy cells. The results of this study combined with literature data show specific gene pathways that might be explored as markers to assess the evolution and prognosis of CML as well as identify new therapeutic targets.

Wiednig M, Beham-Schmid C, Kranzelbinder B, Aberer E
Clonal mast cell proliferation in pruriginous skin in hypereosinophilic syndrome.
Dermatology. 2013; 227(1):67-71 [PubMed] Related Publications
BACKGROUND: Hypereosinophilic syndrome (HES) is defined as a high eosinophilic granulocyte count in peripheral blood and other tissues. It can be associated with clonal and non-clonal haematological neoplastic diseases.
METHODS: Here we present a patient with a 27-year history of pruritus, urticarial lesions, recurrent diarrhoea, depression and a monoclonal gammopathy in the setting of HES.
RESULTS: The patient presented with erythemas, disseminated plaques, papules and scaling. Eosinophils continuously increased from 14% in 2002 to 65% in 2011. Tryptase levels were >20 µg/l. Skin biopsies were unspecific. In the bone marrow biopsy 30% of eosinophilic differentiated precursors and 10% plasma cells were noticed. Skin and bone marrow initially not indicative for mast cell proliferation were investigated for clonal mast cell proliferation. By immunostaining, single tryptase-, CD117c- and CD25-positive mast cells were detected not only in bone marrow, but also in the skin. Molecular investigations revealed a D816V exon 17 mutation of the c-KIT gene in bone marrow and skin biopsies.
CONCLUSION: In this patient HES was associated with high tryptase levels with 2 underlying clonal cell populations - IgGκ-positive plasma cells and single clonal mast cells with a high percentage of eosinophils in the bone marrow with symptoms of a clonal mast cell activation syndrome. Because of 3 minor criteria the patient finally fulfilled the criteria for systemic mastocytosis (according to the WHO). Patients with high tryptase levels and symptoms of mast cell activation syndrome should be investigated for clonal mast cell disease even in the absence of increased mast cells in the skin and bone marrow.

Mascia F, Lam G, Keith C, et al.
Genetic ablation of epidermal EGFR reveals the dynamic origin of adverse effects of anti-EGFR therapy.
Sci Transl Med. 2013; 5(199):199ra110 [PubMed] Related Publications
Cancer patients treated with anti-EGFR (epidermal growth factor receptor) drugs often develop a dose-limiting pruritic rash of unknown etiology. The aims of our study were to define causal associations from a clinical study of cutaneous and systemic changes in patients treated with gefitinib and use these to develop and characterize a mouse model that recapitulates the human skin rash syndrome caused by anti-EGFR therapy. We examined the patients' plasma before and after treatment with gefitinib and documented changes in chemokines and leukocyte counts associated with the extent of rash or the presence of pruritus. We established a parallel mouse model by ablating EGFR in the epidermis. These mice developed skin lesions similar to the human rash. Before lesion development, we detected increased mRNA expression of chemokines in the skin associated with early infiltration of macrophages and mast cells and later infiltration of eosinophils, T cells, and neutrophils. As the skin phenotype evolved, changes in blood counts and circulating chemokines reproduced those seen in the gefitinib-treated patients. Crossing the mutant mice with mice deficient for tumor necrosis factor-α (TNF-α) receptors, MyD88, NOS2, CCR2, T cells, or B cells failed to reverse the skin phenotype. However, local depletion of macrophages provided partial resolution, suggesting that this model can identify targets that may be effective in preventing the troublesome and dose-limiting skin response to anti-EGFR drugs. These results highlight the importance of EGFR signaling in maintaining skin immune homeostasis and identify a macrophage contribution to a serious adverse consequence of cancer chemotherapy.

Li WQ, Hu N, Wang Z, et al.
Genetic variants in epidermal growth factor receptor pathway genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population.
PLoS One. 2013; 8(7):e68999 [PubMed] Free Access to Full Article Related Publications
The epidermal growth factor receptor (EGFR) signaling pathway regulates cell proliferation, differentiation, and survival, and is frequently dysregulated in esophageal and gastric cancers. Few studies have comprehensively examined the association between germline genetic variants in the EGFR pathway and risk of esophageal and gastric cancers. Based on a genome-wide association study in a Han Chinese population, we examined 3443 SNPs in 127 genes in the EGFR pathway for 1942 esophageal squamous cell carcinomas (ESCCs), 1758 gastric cancers (GCs), and 2111 controls. SNP-level analyses were conducted using logistic regression models. We applied the resampling-based adaptive rank truncated product approach to determine the gene- and pathway-level associations. The EGFR pathway was significantly associated with GC risk (P = 2.16×10(-3)). Gene-level analyses found 10 genes to be associated with GC, including FYN, MAPK8, MAP2K4, GNAI3, MAP2K1, TLN1, PRLR, PLCG2, RPS6KB2, and PIK3R3 (P<0.05). For ESCC, we did not observe a significant pathway-level association (P = 0.72), but gene-level analyses suggested associations between GNAI3, CHRNE, PAK4, WASL, and ITCH, and ESCC (P<0.05). Our data suggest an association between specific genes in the EGFR signaling pathway and risk of GC and ESCC. Further studies are warranted to validate these associations and to investigate underlying mechanisms.

Gangemi S, Franchina T, Minciullo PL, et al.
IL-33/IL-31 axis: a new pathological mechanisms for EGFR tyrosine kinase inhibitors-associated skin toxicity.
J Cell Biochem. 2013; 114(12):2673-6 [PubMed] Related Publications
The dermatologic side effects are the most common adverse effects associated with Epidermal Growth Factor Receptor tyrosine kinase inhibitors. Although the mechanisms underlying the development of the skin toxicity remain unclear, immunological mechanisms are considered to be involved. A possible correlation between plasma levels of certain cytokines and development of skin toxicity has been reported. The aim of this work was to investigate the possible contribution of IL-31 and IL-33, cytokines involved in disorders associated with itching, in the pathogenesis of pruritus in patients undergoing EGFR-TK inhibitors. We report a significant increase of IL-31 and IL-33 serum levels in a patient with a bronchioalveolar carcinoma, who had showed previous skin rash, xerosis, and pruritus during treatment with different EGFR-TK inhibitors. She developed intense iching during gefitinib therapy. Therefore, we had collected patient blood sample to evaluate IL-31 and IL-33 serum levels compared to controls, reporting a significant increase in serum of patient. In the light of these findings, EGFR-TK inhibitors-related symptoms of dermatologic toxicities might be related to the release of IL-31 and IL-33. In particular, it is supposable that EGFR-TK inhibitors could cause keratinocytes injury, the release of IL-33 and the consequent interaction with its receptor on mast cells, that induces the secretion of several factors capable to cause skin manifestations, included IL-31, a known pruritus-inducing cytokine. This report, to the best of our knowledge, is the first work describing a possible involvement of IL-31/IL-33 axis in the pathogenesis of skin side effects related to EGFR-TK inhibitors treatment.

Yeung B, Ho KC, Yang X
WWP1 E3 ligase targets LATS1 for ubiquitin-mediated degradation in breast cancer cells.
PLoS One. 2013; 8(4):e61027 [PubMed] Free Access to Full Article Related Publications
The Large Tumor Suppressor 1 (LATS1) is a serine/threonine kinase and tumor suppressor found down-regulated in various human cancers. LATS1 has recently been identified as a central player of the emerging Hippo signaling pathway, which plays important roles in organ size control, tumorigenesis, and stem cell differentiation and renewal, etc. Although mounting evidence supports a role of LATS1 in tumor suppression and tumorigenesis, how LATS1 is regulated at the molecular level is not fully understood. Recently several positive regulators of LATS1 (Mst1/2, MOB1, Kibra, etc) have been identified but how LATS1 is negatively regulated is still largely unknown. We have recently identified Itch, a member of the NEDD4-like family E3 ubiquitin ligases, as a novel negative regulator of LATS1. However, whether other ubiquitin ligases modulate LATS1 stability and function is unclear. By screening many E3 ligases of the NEDD4-like family using over-expression and short-interference RNA knockdown approaches, we have identified WWP1 E3 ligase as another novel negative regulator of LATS1. We have provided in vitro and in vivo evidence that WWP1 is essential for LATS1 stability and negatively regulate LATS1 by promoting LATS1 degradation through polyubiquitination and the 26S proteasome pathway. Importantly, we also showed that degradation of LATS1 is critical in mediating WWP1-induced increased cell proliferation in breast cancer cells. Since WWP1 is an oncogene and LATS1 is a tumor suppressor gene in breast cancer, our studies provide a promising therapeutic strategy in which developed drugs targeting WWP1 cause activation of LATS1 in suppressing breast cancer cell growth.

da Rocha Dias S, Salmonson T, van Zwieten-Boot B, et al.
The European Medicines Agency review of vemurafenib (Zelboraf®) for the treatment of adult patients with BRAF V600 mutation-positive unresectable or metastatic melanoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.
Eur J Cancer. 2013; 49(7):1654-61 [PubMed] Related Publications
The applicant company Roche Registration Ltd. submitted to the European Medicines Agency (EMA) an application for marketing authorisation for vemurafenib. Vemurafenib is a low molecular weight, orally available, inhibitor of oncogenic V600 BRAF serine-threonine kinase. Mutations in the BRAF gene which substitute the valine at amino acid position 600 constitutively activate BRAF proteins, which will drive cell proliferation in the absence of growth factors. Results from a phase 3 trial (N=675) comparing vemurafenib 960 mg twice daily (taken either with or without food) to standard treatment dacarbazine (DTIC) in patients with BRAF V600E mutation-positive unresectable or metastatic melanoma were submitted. The study met its primary efficacy objective after an interim analysis of overall survival. Patients were allowed to cross-over to the experimental arm following disclosure of the study results after the first interim analysis. In the update of the analysis, the median overall survival (OS) was 9.9 months versus 13.2 months for DTIC and vemurafenib, respectively (HR=0.67; 95% confidence interval (CI): 0.54, 0.84; cut-off 3 October 2011). Based on the updated analysis, the CHMP concluded that a survival benefit over DTIC had been convincingly demonstrated, in the overall population. The follow-up was considered sufficiently mature with close to 50% of the events observed. The most common side effects (affecting more than 30% of patients) in vemurafenib treated patients included arthralgia, fatigue, rash, photosensitivity reaction, nausea, alopecia and pruritus. Some patients treated with vemurafenib developed cutaneous squamous cell carcinoma which was readily treated by local surgery. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the European Union (EU). The full scientific assessment report and product information, including the Summary of Product Characteristics (SmPC), are available on the EMA website (www.ema.europa.eu).

Bozóky B, Savchenko A, Csermely P, et al.
Novel signatures of cancer-associated fibroblasts.
Int J Cancer. 2013; 133(2):286-93 [PubMed] Related Publications
Increasing evidence indicates the importance of the tumor microenvironment, in particular cancer-associated fibroblasts, in cancer development and progression. In our study, we developed a novel, visually based method to identify new immunohistochemical signatures of these fibroblasts. The method employed a protein list based on 759 protein products of genes identified by RNA profiling from our previous study, comparing fibroblasts with differential growth-modulating effect on human cancers cells, and their first neighbors in the human protein interactome. These 2,654 proteins were analyzed in the Human Protein Atlas online database by comparing their immunohistochemical expression patterns in normal versus tumor-associated fibroblasts. Twelve new proteins differentially expressed in cancer-associated fibroblasts were identified (DLG1, BHLHE40, ROCK2, RAB31, AZI2, PKM2, ARHGAP31, ARHGAP26, ITCH, EGLN1, RNF19A and PLOD2), four of them can be connected to the Rho kinase signaling pathway. They were further analyzed in several additional tumor stromata and revealed that the majority showed congruence among the different tumors. Many of them were also positive in normal myofibroblast-like cells. The new signatures can be useful in immunohistochemical analysis of different tumor stromata and may also give us an insight into the pathways activated in them in their true in vivo context. The method itself could be used for other similar analysis to identify proteins expressed in other cell types in tumors and their surrounding microenvironment.

Song L, Lin C, Gong H, et al.
miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops.
Cell Res. 2013; 23(2):274-89 [PubMed] Free Access to Full Article Related Publications
Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

Manousaridis I, Mavridou S, Goerdt S, et al.
Cutaneous side effects of inhibitors of the RAS/RAF/MEK/ERK signalling pathway and their management.
J Eur Acad Dermatol Venereol. 2013; 27(1):11-8 [PubMed] Related Publications
Mutations in genes encoding for proteins along the RAS-RAF-MEK-ERK pathway have been detected in a variety of tumor entities, including malignant melanoma, thyroid, colonic and ovarian carcinomas, and some sarcomas. Thus, a number of inhibitors of this pathway have been developed, whose antitumor potential is currently being assessed in different clinical trials. Up to now one drug of this category (vemurafenib) has been approved by the FDA and the European Commission for late-stage melanoma. Although these new targeted anticancer therapies are generally considered to be safe and well tolerated, certain toxicities have been attributed to them, with cutaneous side effects being perhaps the most frequent amongst them. Based on results of clinical trials and on case series, a distinct profile of cutaneous toxicity has been observed, which is similar to that of EGFR and multikinase inhibitors. As exanthema, palmar-plantar erythrodysesthesia syndrome, hyperkeratosis, xerosis, pruritus, photosensitivity, and paronychia, can be controlled in most cases with common conservative modalities, special attention should be given to the early detection of epithelial skin tumors (mainly keratoakanthomas) that can be induced during therapy with these agents. This report reviews all current published data on cutaneous side effects of RAS-RAF-MEK-ERK pathway inhibitors, and attempts to provide the clinician with clear hints for their management.

Subik K, Shu L, Wu C, et al.
The ubiquitin E3 ligase WWP1 decreases CXCL12-mediated MDA231 breast cancer cell migration and bone metastasis.
Bone. 2012; 50(4):813-23 [PubMed] Free Access to Full Article Related Publications
Advanced breast cancers preferentially metastasize to bone where cells in the bone microenvironment produce factors that enhance breast cancer cell homing and growth. Expression of the ubiquitin E3 ligase WWP1 is increased in some breast cancers, but its role in bone metastasis has not been investigated. Here, we studied the effects of WWP1 and itch, its closest family member, on breast cancer bone metastasis. First, we immunostained a multi-tumor tissue microarray and a breast cancer tissue microarray and demonstrated that WWP1 and ITCH are expressed in some of breast cancer cases. We then knocked down WWP1 or itch in MDA-MB-231 breast cancer cells using shRNA and inoculated these cells and control cells into the left ventricle of athymic nude mice. Radiographs showed that mice given shWWP1 cells had more osteolytic lesions than mice given control MDA-MB-231 cells. Histologic analysis confirmed osteolysis and showed significantly increased tumor area in bone marrow of the mice. WWP1 knockdown did not affect cell growth, survival or osteoclastogenic potential, but markedly increased cell migration toward a CXCL12 gradient in vitro. Furthermore, WWP1 knockdown significantly reduced CXCL12-induced CXCR4 lysosomal trafficking and degradation. In contrast, itch knockdown had no effect on MDA-MB-231 cell bone metastasis. Taken together, these findings demonstrate that WWP1 negatively regulates cell migration to CXCL12 by limiting CXCR4 degradation to promote breast cancer metastasis to bone and highlight the potential utility of WWP1 as a prognostic indicator for breast cancer bone metastasis.

Dummer R, Beyer M, Hymes K, et al.
Vorinostat combined with bexarotene for treatment of cutaneous T-cell lymphoma: in vitro and phase I clinical evidence supporting augmentation of retinoic acid receptor/retinoid X receptor activation by histone deacetylase inhibition.
Leuk Lymphoma. 2012; 53(8):1501-8 [PubMed] Related Publications
The retinoid X receptor (RXR)-agonist bexarotene and the histone deacetylase inhibitor (HDACI) vorinostat are each established monotherapies for cutaneous T-cell lymphomas (CTCLs). We investigated the combination of HDACI and retinoic acid receptor (RAR)/RXR agonists in vitro and in a phase I, multicenter, open-label, two-part dose-escalation study. The combination of bexarotene with a HDACI in vitro leads to cooperative activation of gene transcription and reduction of cell viability in human tumor cell lines. The primary clinical objective was to determine the maximum tolerated dose (MTD) of bexarotene plus vorinostat in 23 patients with CTCLs. The MTD for part I was established at vorinostat 200 mg/day plus bexarotene 300 mg/m(2)/day. The MTD for part II was not reached. Four patients had an objective response and seven patients experienced pruritus relief. We conclude that concomitant administration of vorinostat and bexarotene is feasible only if lower doses of each drug are administered relative to the product label monotherapy doses.

Miyagaki T, Sugaya M, Suga H, et al.
IL-22, but not IL-17, dominant environment in cutaneous T-cell lymphoma.
Clin Cancer Res. 2011; 17(24):7529-38 [PubMed] Related Publications
PURPOSE: Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, T(H)2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22-producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of T(H)22- and T(H)17-related molecules in lesional skin and sera isolated from patients with CTCL.
EXPERIMENTAL DESIGN: Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry.
RESULTS: IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity.
CONCLUSIONS: Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6(+) cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL.

Pollyea DA, Kohrt HE, Gallegos L, et al.
Safety, efficacy and biological predictors of response to sequential azacitidine and lenalidomide for elderly patients with acute myeloid leukemia.
Leukemia. 2012; 26(5):893-901 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a disease of the elderly. Poor outcomes with standard therapies necessitate novel approaches. Outpatient regimens sufficiently potent and well tolerated to induce remissions and enable continuation therapy may be beneficial. In this phase-1 study, we determined the maximum tolerated dose (MTD) and the efficacy for sequential azacitidine and lenalidomide as remission induction and continuation therapy in elderly, previously untreated patients. We investigated the impact on global DNA methylation and bone marrow cytokines, and sought biological predictors of response. Eighteen patients were enrolled. The MTD was not reached. Median follow-up was 8.2 months (10.3 months for survivors). Common adverse events included fatigue, injection site reactions, constipation, nausea, pruritus and febrile neutropenia. Ten patients responded (56%), and the rate of complete remissions (CRs) or CRs with incomplete recovery of blood counts for evaluable patients was 44% (7/16). The median response duration was 6.2 months. DNA demethylation and changes in bone marrow cytokines were observed; responders had a unique cytokine profile and a trend towards lower methylation levels. Sequential azacitidine and lenalidomide was well tolerated with encouraging clinical and biological activity in previously untreated elderly AML patients. This trial is registered at ClinicalTrials.gov (NCT00890929).

Ishihara T, Inoue J, Kozaki K, et al.
HECT-type ubiquitin ligase ITCH targets lysosomal-associated protein multispanning transmembrane 5 (LAPTM5) and prevents LAPTM5-mediated cell death.
J Biol Chem. 2011; 286(51):44086-94 [PubMed] Free Access to Full Article Related Publications
LAPTM5 (lysosomal-associated protein multispanning transmembrane 5) is a membrane protein on the intracellular vesicles. We have previously demonstrated that the accumulation of LAPTM5-positive vesicles was closely associated with the programmed cell death occurring during the spontaneous regression of neuroblastomas. Although the accumulation of LAPTM5 protein might occur at the post-translational level, the molecular mechanism has been unclear. Here, we found that the level of LAPTM5 protein is regulated negatively by the degradation through ubiquitination by ITCH, an E3 ubiquitin ligase. ITCH directly binds to the PPxY motif of LAPTM5 via its WW domains and promotes ubiquitination through a HECT-type ligase domain. Overexpression of ITCH led to the degradation of LAPTM5 protein, and conversely, knockdown of ITCH by siRNA resulted in the stabilization of LAPTM5 protein. In addition, the inhibition of ITCH enhanced the cell death occurred by accumulation of LAPTM5 in neuroblastoma cells. These findings suggest that LAPTM5 is a novel substrate in terms of degradation by the ubiquitin ligase ITCH, and this system might act as a negative regulator in the spontaneous regression of neuroblastomas by preventing LAPTM5-mediated cell death.

Kleewein K, Lang R, Diem A, et al.
Diffuse cutaneous mastocytosis masquerading as epidermolysis bullosa.
Pediatr Dermatol. 2011 Nov-Dec; 28(6):720-5 [PubMed] Related Publications
A 10-month-old boy presented with a history of a generalized cutaneous bullous eruption since 3 months of age. Emesis, flush, pruritus, and fatigue had accompanied relapsing episodes of sometimes extensive blistering. Histopathology showed dense dermal infiltrates of mast cells on hematoxylin and eosin and corroborating immunohistochemical staining. Laboratory examination revealed a markedly high level of serum tryptase. Based on these results and after consecutive staging, the patient was diagnosed with diffuse cutaneous bullous mastocytosis (BM). Mutation analysis detected a deletion mutation (del419) in C-Kit by direct exon sequencing. This rare entity must be considered in the differential diagnosis whenever a child presents with bullae and erosions. A crucial diagnostic hint is that rubbing of affected skin areas results in whealing (Darier's sign). A comprehensive diagnostic approach, advanced therapeutic strategies, regular follow-ups, and instruction of patients and relatives on prevention and prophylaxis are highly indicated.

Balaraman B, Conley JA, Sheinbein DM
Evaluation of cutaneous angioimmunoblastic T-cell lymphoma.
J Am Acad Dermatol. 2011; 65(4):855-62 [PubMed] Related Publications
BACKGROUND: Angioimmunoblastic T-cell lymphoma (AITL) accounts for 18% of peripheral T-cell lymphomas worldwide. Skin involvement occurs in up to 50% of patients but poses a diagnostic dilemma because of the limited number of reported cases and subsequent lack of established diagnostic criteria.
OBJECTIVE: The purpose of this review is to examine common clinical, histologic, and molecular findings in cases of AITL with the hope of improving the diagnostic accuracy of this challenging condition.
METHODS: We present a case of AITL and conducted a review of the literature.
RESULTS: The common clinical and histologic features in cases of AITL are nonspecific. However, newer immunohistochemical stains and gene rearrangement studies appear very promising at improving diagnostic capabilities.
LIMITATIONS: There was a paucity of reported cases of AITL in the literature, and this review is retrospective.
CONCLUSION: AITL presents with nonspecific clinical and histologic findings, but immunohistochemical stains and gene rearrangements can help establish the diagnosis.

Durrington HJ, Upton PD, Hoer S, et al.
Identification of a lysosomal pathway regulating degradation of the bone morphogenetic protein receptor type II.
J Biol Chem. 2010; 285(48):37641-9 [PubMed] Free Access to Full Article Related Publications
Bone morphogenetic proteins (BMPs) are critically involved in early development and cell differentiation. In humans, dysfunction of the bone morphogenetic protein type II receptor (BMPR-II) is associated with pulmonary arterial hypertension (PAH) and neoplasia. The ability of Kaposi sarcoma-associated herpesvirus (KSHV), the etiologic agent of Kaposi sarcoma and primary effusion lymphoma, to down-regulate cell surface receptor expression is well documented. Here we show that KSHV infection reduces cell surface BMPR-II. We propose that this occurs through the expression of the viral lytic gene, K5, a ubiquitin E3 ligase. Ectopic expression of K5 leads to BMPR-II ubiquitination and lysosomal degradation with a consequent decrease in BMP signaling. The down-regulation by K5 is dependent on both its RING domain and a membrane-proximal lysine in the cytoplasmic domain of BMPR-II. We demonstrate that expression of BMPR-II protein is constitutively regulated by lysosomal degradation in vascular cells and provide preliminary evidence for the involvement of the mammalian E3 ligase, Itch, in the constitutive degradation of BMPR-II. Disruption of BMP signaling may therefore play a role in the pathobiology of diseases caused by KSHV infection, as well as KSHV-associated tumorigenesis and vascular disease.

Amon U, Hartmann K, Horny HP, Nowak A
Mastocytosis - an update.
J Dtsch Dermatol Ges. 2010; 8(9):695-711; quiz 712 [PubMed] Related Publications
Mastocytosis (MC) encompasses a range of disorders characterized by a clonal, pathological accumulation of mast cells having a somatic activating mutation of the tyrosine kinase receptor Kit (exon 17, codon 816; D816V) in more than 90 % of adult patients. The mutation is much less common in children. Skin and bone marrow are most often affected. Symptoms and clinical course are very heterogeneous due to a variable degree of local or systemic mediator release or organ dysfunction as a result of mast cell infiltrates. Pruritus, wheals, flushing and gastrointestinal symptoms are often reported. The majority of pediatric patients experience spontaneous remission of MC. Adults usually have chronic disease, rarely transforming into an aggressive or lethal type. Indolent systemic MC with involvement of skin and bone is the most common type. In MC the risk for anaphylactic reactions following an insect sting (and other causes of mast cell activation) is increased significantly. Diagnostic hallmarks are biopsies from skin and bone marrow using tryptase antibodies for staining as well as serum tryptase levels. At present a curative treatment for MC is not available. Systemic histamine H(1) receptor antagonists are widely used. Aggressive types of MC respond partially to IFN-alpha or cladribine. A variety of receptor tyrosine kinase inhibitors is still under critical evaluation for systemic treatment of MC. After introduction of the WHO classification for MC and the development a German MC guideline, as well as the foundation of national and international competence networks for MC, a significantly improved quality of medical care for MC patients can be expected for the future.

Verstrepen L, Verhelst K, van Loo G, et al.
Expression, biological activities and mechanisms of action of A20 (TNFAIP3).
Biochem Pharmacol. 2010; 80(12):2009-20 [PubMed] Related Publications
A20 (also known as TNFAIP3) is a cytoplasmic protein that plays a key role in the negative regulation of inflammation and immunity. Polymorphisms in the A20 gene locus have been identified as risk alleles for multiple human autoimmune diseases, and A20 has also been proposed to function as a tumor suppressor in several human B-cell lymphomas. A20 expression is strongly induced by multiple stimuli, including the proinflammatory cytokines TNF and IL-1, and microbial products that trigger pathogen recognition receptors, such as Toll-like receptors. A20 functions in a negative feedback loop, which mediates its inhibitory functions by downregulating key proinflammatory signaling pathways, including those controlling NF-κB- and IRF3-dependent gene expression. Activation of these transcription factors is controlled by both K48- and K63- polyubiquitination of upstream signaling proteins, respectively triggering proteasome-mediated degradation or interaction with other signaling proteins. A20 turns off NF-κB and IRF3 activation by modulating both types of ubiquitination. Induction of K48-polyubiquitination by A20 involves its C-terminal zinc-finger ubiquitin-binding domain, which may promote interaction with E3 ligases, such as Itch and RNF11 that are involved in mediating A20 inhibitory functions. A20 is thought to promote de-ubiquitination of K63-polyubiquitin chains either directly, due to its N-terminal deubiquitinase domain, or by disrupting the interaction between E3 and E2 enzymes that catalyze K63-polyubiquitination. A20 is subject to different mechanisms of regulation, including phosphorylation, proteolytic processing, and association with ubiquitin binding proteins. Here we review the expression and biological activities of A20, as well as the underlying molecular mechanisms.

Möbs M, Knott M, Fritzen B, et al.
Diagnostic tools in Sezary syndrome.
G Ital Dermatol Venereol. 2010; 145(3):385-91 [PubMed] Related Publications
Primary cutaneous T-cell lymphomas (CTCL) mycosis fungoides (Mf) and Sézary syndrome (SS) belong to the group of non-Hodgkin lymphomas which are characterized by clonally proliferating CD4+ cells localized in the skin. SS is a leukemic variant of CTCL and is characterized by erythroderma, generalized lymphadenopathy, and circulating atypical T-cells with cerebriform nuclei, so-called Sézary cells. Palmoplantar hyperkeratosis, generalized alopecia, and severe pruritus are additional symptoms that are associated with SS. Patients have a poor prognosis with an estimated five year survival of 12.5 to 27 percent and estimated median survival of 14.5 to 18 months. The incidence of MF and also SS has increased with time and may be in part due to improved clinical awareness and especially advances in diagnostic testing.

Pene-Dumitrescu T, Smithgall TE
Expression of a Src family kinase in chronic myelogenous leukemia cells induces resistance to imatinib in a kinase-dependent manner.
J Biol Chem. 2010; 285(28):21446-57 [PubMed] Free Access to Full Article Related Publications
The Bcr-Abl kinase inhibitor imatinib is remarkably effective in chronic myelogenous leukemia (CML), although drug resistance is an emerging problem. Myeloid Src family kinases such as Hck and Lyn are often overexpressed in imatinib-resistant CML cells that lack Bcr-Abl mutations. Here we tested whether Hck overexpression is sufficient to induce imatinib resistance using both wild-type Hck and a mutant (Hck-T338A) that is uniquely sensitive to the pyrazolo-pyrimidine inhibitor, NaPP1. Expression of either kinase in K562 CML cells caused resistance to imatinib-induced apoptosis and inhibition of soft-agar colony formation. Treatment with NaPP1 restored sensitivity to imatinib in cells expressing T338A but not wild-type Hck, demonstrating that resistance requires Hck kinase activity. NaPP1 also reduced Hck-mediated phosphorylation of Bcr-Abl at sites that may affect imatinib sensitivity exclusively in cells expressing Hck-T338A. These data show that elevated Src family kinase activity is sufficient to induce imatinib resistance through a mechanism that may involve phosphorylation of Bcr-Abl.

Yang F, Tay KH, Dong L, et al.
Cystatin B inhibition of TRAIL-induced apoptosis is associated with the protection of FLIP(L) from degradation by the E3 ligase itch in human melanoma cells.
Cell Death Differ. 2010; 17(8):1354-67 [PubMed] Related Publications
Past studies have identified a number of distinct mechanisms that contribute to the resistance of melanoma cells against apoptosis induced by TNF-related apoptosis-inducing ligand (TRAIL). In this report we show that cystatin B is another endogenous inhibitor of TRAIL-induced apoptosis. Cystatin B-deficient melanoma cell lines established by shRNA knockdown displayed increased apoptosis that was associated with enhanced activation of caspase-8 induced by TRAIL. This was not related to the inhibitory effect of cystatin B on the lysosomal cysteine proteases, cathepsin B and L, as they did not have a role in TRAIL-induced apoptosis in most melanoma cell lines even when cystatin B was inhibited. Instead, sensitization of melanoma cells to TRAIL-induced apoptosis by inhibition of cystatin B appeared associated with decreased stability of FLIP(L) as the levels of FLIP(L) were reduced because of shortened half-life time in melanoma cells deficient in cystatin B. In contrast, over-expression of cystatin B increased the levels of FLIP(L), decreased the amount of the E3 ligase Itch associated with FLIP(L), and reduced FLIP(L) ubiquitination. Inhibition of Itch by siRNA restored the levels of FLIP(L) and blocked sensitization to TRAIL-induced apoptosis associated with deficiency in cystatin B. Taken together, these results indicate that cystatin B regulates Itch-mediated degradation of FLIP(L) and thereby TRAIL-induced apoptosis in melanoma cells.

Tophkhane C, Yang S, Zhao ZJ, Yang X
Cell density-dependent regulation of p73 in breast cancer cells.
Int J Oncol. 2009; 35(6):1429-34 [PubMed] Related Publications
Molecular regulation of p73, a p53 family member, remains unclear. Here we report that p73 expression is significantly regulated by cell densities. In particular, we found that p73alpha and p73beta are differentially regulated. While p73beta protein levels were inversely correlated with cell densities, p73alpha protein levels behaved oppositely. We further showed that density-dependent changes of p73alpha follow the same patterns as E2F-1 and TAp73 mRNA levels, suggesting transcriptional regulation. Our data also suggest that high levels of p73beta at lower densities may be due to increased protein stability. However, AIP-4/Itch appeared not to be involved in downregulation of p73beta at high densities. Moreover, we also found that subcellular location of p73 isoforms changes with the culture density increases. While high level of p73beta at low density was mainly presented in the nucleus, low levels of this protein at high densities were mainly in the cytosol. Taken together, these findings reveal a novel mechanism that differentially regulates p73 isoforms and underscores the role of cell-cell interaction in p73 regulation, which may advance our understanding of p73 expression and function in human cancers.

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