Alternative Splicing Determines the Domain Structure of WWP1, a Nedd4 Family Protein

Flasza, Marzena; Gorman, Patricia; Roylance, Rebecca; Canfield, Ann E.; Baron, Martín

doi:10.1006/bbrc.2001.6206

Cited by 41 publications

(36 citation statements)

References 33 publications

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“…Different isoforms have different domain structures and thus may function differently. Although a previous study of the breast cancer cell line T-47D suggests the presence of tumorspecific splicing of WWP1 (Flasza et al, 2002), our northern blot analysis showed that a smaller isoform of WWP1 is present in both normal and cancer cells, and this isoform is not related to cancer (Figure 2b). In addition, wild-type WWP1 is the dominant form that is overexpressed in some cancer samples.…”

Section: Discussioncontrasting

confidence: 77%

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Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer

et al. 2006

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The gene for E3 ubiquitin ligase WWP1 is located at 8q21, a region frequently amplified in human cancers, including prostate cancer. Recent studies have shown that WWP1 negatively regulates the TGFb tumor suppressor pathway by inactivating its molecular components, including Smad2, Smad4 and TbR1. These findings suggest an oncogenic role of WWP1 in carcinogenesis, but direct supporting evidence has been lacking. In this study, we examined WWP1 for gene dosage, mRNA expression, mutation and functions in a number of human prostate cancer samples. We found that the WWP1 gene had copy number gain in 15 of 34 (44%) xenografts and cell lines from prostate cancer and 15 of 49 (31%) clinical prostate cancer samples. Consistently, WWP1 was overexpressed in 60% of xenografts and cell lines from prostate cancer. Mutation of WWP1 occurred infrequently in prostate cancer. Functionally, WWP1 overexpression promoted colony formation in the 22Rv1 prostate cancer cell line. In PC-3 prostate cancer cells, WWP1 knockdown significantly suppressed cell proliferation and enhanced TGFb-mediated growth inhibition. These findings suggest that WWP1 is an oncogene that undergoes genomic amplification at 8q21 in human prostate cancer, and WWP1 overexpression is a common mechanism involved in the inactivation of TGFb function in human cancer.

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Section: Discussioncontrasting

confidence: 77%

“…WWP1 has multiple isoforms resulting from alternative splicing (Flasza et al, 2002). Different isoforms have different domain structures and thus may function differently.…”

Section: Discussionmentioning

confidence: 99%

Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer

et al. 2006

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“…24 Our Northern blot analysis showed that a smaller isoform of WWP1, indicated as a band below the wild type WWP1 mRNA at 4.2 Kb, was detected in some samples. However, the isoform was not associated with breast cancer because it was present in both cancer samples and nontumor controls (Fig.…”

Section: Expression Of Wwp1 Is Frequently Up-regulated In Breast Cancermentioning

confidence: 65%

The amplified WWP1 gene is a potential molecular target in breast cancer

Chen

Zhou

Ross

et al. 2007

Intl Journal of Cancer

126

136

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The amplification of the q21 band of chromosome 8 (8q21) occurs in a large percentage of breast cancers. WWP1, an HECT domain-containing ubiquitin E3 ligase located in the 8q21 region, negatively regulates the TGF-b tumor suppressor pathway. To characterize the role of WWP1 in breast cancer, we analyzed WWP1 gene dosage and expression level as well as WWP1's function. A copy number gain of WWP1 was found in 51% (18/35) of breast cancer cell lines and in 41% (17/41) of primary breast tumors. Expression of WWP1 mRNA was analyzed with real-time RT-PCR, Northern blot, and Western blot. WWP1 mRNA is upregulated in 58% (19/33) of breast cancer cell lines, and overexpression of WWP1 is significantly correlated with a gene copy number gain. In a panel of cDNA from primary breast tumors and normal tissues, expression of WWP1 in tumors is significantly higher than that in normal tissues. Functionally, RNAi-mediated WWP1 knockdown significantly induced cell growth arrest and apoptosis in the MCF7 and HCC1500 breast cancer cell lines. Consistently, WWP1 inhibition activated caspases. Forced overexpression of WWP1 by the lentiviral system in 2 immortalized breast epithelial cell lines MCF10A and 184B5 promoted cell proliferation. These results suggest that genomic aberrations of WWP1 may contribute to the pathogenesis of breast cancer. ' 2007 Wiley-Liss, Inc.Key words: WWP1; breast cancer; gene amplification; overexpression; apoptosis A copy number gain or loss is a frequent genetic alteration in solid tumors including breast cancer. A copy number gain of 8q21 was detected in a high percentage of familial and sporadic breast tumors.1-3 Although several 8q21 genes, such as TPD52 and E2F5, have been reported to be amplified and overexpressed in breast cancer, 4,5 their roles have not been firmly established in breast tumorigenesis, and the underlying target genes of 8q21 amplification in breast cancer remain to be elucidated.Ubiquitin proteasome pathway (UPP)-mediated protein degradation plays an important role in breast cancer cell proliferation, apoptosis and carcinogenesis.6 Several oncogenic ubiquitin E3 ligases have been identified as diagnosis markers or potential drug targets in human breast cancer.7 For example, Skp2, an F-box protein in the SCF ubiquitin ligase complex, targets the CDK inhibitor p27 kip for degradation and is overexpressed in a subset of breast carcinomas. 8 The ring finger E3 ligase EFP mediates estrogen-induced cell growth and facilitates 14-3-3r tumor suppressor ubiquitination and proteolysis.9 EFP mRNA and protein were reported to be overexpressed and significantly correlated with poor prognosis of breast cancer patients. 10WW domain-containing protein 1 (WWP1) is an HECT (homologous to the E6-associated protein carboxyl terminus) domain-containing E3 ubiquitin ligase. Growing evidence suggests that WWP1 negatively regulates the TGF-b tumor suppressor pathway by mediating the ubiquitination and degradation of TGFb receptor 1 (TbR1), In our previous study, we found that WWP1 is amplified and overe...

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“…The domain structure of human WWP1 was determined previously [12]. It consists of three types of unique domains: one C2 domain, four WW domains and one HECT domain.…”

Section: Mutations Specific To Muscular Dystrophymentioning

confidence: 99%

The ubiquitin ligase gene (WWP1) is responsible for the chicken muscular dystrophy

et al. 2008

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Chicken muscular dystrophy with abnormal muscle (AM) has been studied for more than 50 years, but the gene responsible for it remains unclear. Our previous studies narrowed down the AM candidate region to approximately 1 Mbp of chicken chromosome 2q containing seven genes. In this study, we performed sequence comparison and gene expression analysis to elucidate the responsible gene. One missense mutation was detected in AM candidate genes, while no remarkable alteration of expression patterns was observed. The mutation was identified in WWP1, detected only in dystrophic chickens within several tetrapods. These results suggested WWP1 is responsible for chicken muscular dystrophy.

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Alternative Splicing Determines the Domain Structure of WWP1, a Nedd4 Family Protein

Cited by 41 publications

References 33 publications

Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer

Ubiquitin E3 ligase WWP1 as an oncogenic factor in human prostate cancer

The amplified WWP1 gene is a potential molecular target in breast cancer

The ubiquitin ligase gene (WWP1) is responsible for the chicken muscular dystrophy

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