A gene from human chromosome 11 p11.2 was isolated and was shown to suppress metastasis when introduced into rat AT6.1 prostate cancer cells. Expression of this gene, designated KA11, was reduced in human cell lines derived from metastatic prostate tumors. KA11 specifies a protein of 267 amino acids, with four hydrophobic and presumably transmembrane domains and one large extracellular hydrophilic domain with three potential N-glycosylation sites. KA11 is evolutionarily conserved, is expressed in many human tissues, and encodes a member of a structurally distinct family of leukocyte surface glycoproteins. Decreased expression of this gene may be involved in the malignant progression of prostate and other cancers. (3), and the putative metastasis suppressor gene was mapped to human chromosome llpll.2-13 (the pl1.2-13 region of chromosome 11) by microcell-mediated chromosome transfer (4).To clone this metastasis suppressor gene on human chromosome 11, we isolated genomic DNA fragments from the pl 1.2-13 region by human-specific Alu element-me-
KLF5 (Kruppel-like factor 5) is a basic transcription factor binding to GC boxes at a number of gene promoters and regulating their transcription. KLF5 is expressed during development and, in adults, with higher levels in proliferating epithelial cells. The expression and activity of KLF5 are regulated by multiple signaling pathways, including Ras/MAPK, PKC, and TGFbeta, and various posttranslational modifications, including phosphorylation, acetylation, ubiquitination, and sumoylation. Consistently, KLF5 mediates the signaling functions in cell proliferation, cell cycle, apoptosis, migration, differentiation, and stemness by regulating gene expression in response to environment stimuli. The expression of KLF5 is frequently abnormal in human cancers and in cardiovascular disease-associated vascular smooth muscle cells (VSMCs). Due to its significant functions in cell proliferation, survival, and differentiation, KLF5 could be a potential diagnostic biomarker and therapeutic target for cancer and cardiovascular diseases.
The 13q21 tumor suppressor locus, as defined by chromosomal deletion, harbors the KLF5 transcription factor which may have tumor suppressor function. To investigate whether KLF5 plays a role in breast cancer, we evaluated all genes and/or expressed sequence tags (ESTs) within a 3.3 Mb common region of deletion at 13q21. Of these, only KLF5 mRNA was expressed at high levels in non-neoplastic breast epithelial cells and in normal human mammary tissue, but at lower levels in various breast cancer cell lines. Using the real time TaqMan PCR assay, hemizygous deletion at KLF5 was detected in 13 out of 30, or 43% of breast cancer cell lines tested, and various degrees of loss of expression were detected in 21 out of 30, or 70% of these cell lines. Each of the cases with hemizygous deletion also exhibited loss of KLF5 expression, suggesting that loss of expression can result from chromosomal deletion, and that KLF5 may undergo haploinsufficiency during carcinogenesis. Only one of the 30 breast cancer cell lines tested exhibited a mutation in KLF5, and neither promoter methylation nor homozygous deletion was detected in any of the cell lines. In contrast, loss of heterozygosity (LOH) was frequently detected at KLF5. Re-expression of wild-type KLF5 in T-47D breast cancer cells significantly inhibited colony formation in these cells. Of the KLF5-transfected clones that did form colonies, none were found to express KLF5 mRNA. These findings suggest that loss of function by deletion and/or loss of expression frequently occurs at KLF5, and KLF5 suppresses tumor cell growth in breast cancer.
Frequent genomic deletion and loss of expression as well as cell growth suppression indicate that KLF5 is a reasonable candidate for the tumor suppressor gene at 13q21 in prostate cancer. Mutation and promoter methylation are not common mechanisms for the inactivation of KLF5 in prostate cancer.
Quantitative and structural genetic alterations cause the development and progression of prostate cancer.
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...
We report a previously unrecognized prostate-specific protein, PrLZ (prostate leucine zipper), a new member of the Tumor Protein D52 (TPD52) family. The gene for PrLZ was localized at chromosome 8q21.1, a locus most frequently amplified in human prostate cancer. Multiple tissue analyses demonstrated PrLZ predominantly in the prostate gland. Although its expression was enhanced by androgens in androgen receptor-expressing cells, PrLZ was detected in all of the human prostate cancer cell lines, regardless of androgen receptor status. Monoclonal anti-PrLZ antibodies were produced and intense immunohistochemical staining of PrLZ was observed in prostate epithelial cells in intraepithelial neoplasia and prostate cancer, whereas lower-level staining was detected in normal and benign epithelial components of the prostate gland. As the only prostate-specific gene identified in the most frequently amplified genomic region in prostate cancer, PrLZ may be the link between chromosome 8q amplification and malignant transformation of the prostate epithelia.
The familial cylindromatosis tumor suppressor CYLD is known to contain three cytoskeleton-associated protein glycine-rich (CAP-Gly) domains, which exist in a number of microtubule-binding proteins and are responsible for their association with microtubules. However, it remains elusive whether CYLD interacts with microtubules and, if so, whether the interaction is mediated by the CAP-Gly domains. In this study, our data demonstrate that CYLD associates with microtubules both in cells and in vitro, and the first CAP-Gly domain of CYLD is mainly responsible for the interaction. Knockdown of cellular CYLD expression dramatically delays microtubule regrowth after nocodazole washout, indicating an activity for CYLD in promoting microtubule assembly. Our data further demonstrate that CYLD enhances tubulin polymerization into microtubules by lowering the critical concentration for microtubule assembly. In addition, we have identified by wound healing assay a critical role for CYLD in mediating cell migration and found that its first CAP-Gly domain is required for this activity. Thus CYLD joins a growing list of CAP-Gly domain-containing proteins that regulate microtubule dynamics and function.
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