<i>KLF5</i> is frequently deleted and down‐regulated but rarely mutated in prostate cancer

Chen, Ceshi; Bhalala, Hina V.; Vessella, Robert L.; Dong, Jin‐Tang

doi:10.1002/pros.10205

Cited by 126 publications

(184 citation statements)

References 34 publications

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“…All breast and prostate cell lines have been described in our previous studies. 3,43,44 The human embryonic kidney 293T-derived LinX cell line was cultured in DMEM containing 5% fetal bovine serum (FBS) and 1% penicillin and streptomycin (PS). The p53 wild type (WT) and p53-null HCT116 colon cancer cell lines were grown in HyQ s McCOY'S 5A medium with 5% FBS and 1% PS.…”

Section: Methodsmentioning

confidence: 99%

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

2008

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WWP1 E3 ubiquitin ligase has previously been shown to be frequently amplified and overexpressed in prostate and breast cancers. However, the mechanism of WWP1 action is still largely unknown. p63, a member of the p53 family of transcription factors, has an important function in tumor development by regulating apoptosis. Using alternative promoters, p63 can be expressed as DNp63 and TAp63. Increasing evidence suggests that TAp63 sensitizes cells to apoptosis but DNp63 has an opposite function. In this study, we show that WWP1 binds, ubiquitinates, and destructs both DNp63a and TAp63a. The proteinprotein interaction occurs between the PY motif of p63 and the WW domains of WWP1. The knockdown of WWP1 by siRNA increases the endogenous DNp63a level in the MCF10A and 184B5 immortalized breast epithelial cell lines and confers resistance to doxorubicin-induced apoptosis. On the other hand, the knockdown of WWP1 increases the endogenous level of TAp63a, induces apoptosis, and increases sensitivity to doxorubicin and cisplatin in the HCT116 colon cancer cell line in a p53-independent manner. Finally, we found that DNA damage chemotherapeutic drugs induce WWP1 mRNA and protein expression in a p53-dependent manner. These data suggest that WWP1 may have a context-dependent role in regulating cell survival through targeting different p63 proteins for degradation.

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Section: Methodsmentioning

confidence: 99%

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

2008

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“…KLF4 mRNA and protein levels are also increased during progression of breast cancer [35], and nuclear localization of KLF4 is associated with an aggressive phenotype in early stage breast cancer [36]. In contrast to the pro-proliferative effect of KLF5 shown above, loss of KLF5 expression has been observed in prostate [37] and breast cancer [38]. Moreover, KLF5 has been shown to reduce colony formation in transformed intestinal epithelial cells [39].…”

Section: Can Klf4 and Klf5 Reverse Their Biological Behavior In Certamentioning

confidence: 99%

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

et al. 2005

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Krüppel-like factors (KLFs) are evolutionarily conserved zinc finger-containing transcription factors with diverse regulatory functions in cell growth, proliferation, differentiation, and embryogenesis. KLF4 and KLF5 are two closely related members of the KLF family that have a similar tissue distribution in embryos and adults. However, the two KLFs often exhibit opposite effects on regulation of gene transcription, despite binding to similar, if not identical, cis-acting DNA sequences. In addition, KLF4 and 5 exert contrasting effects on cell proliferation in many instances; while KLF4 is an inhibitor of cell growth, KLF5 stimulates proliferation. Here we review the biological properties and biochemical mechanisms of action of the two KLFs in the context of growth regulation.

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“…2C). Finally, WWP1 also efficiently targeted KLF5DN [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] for degradation like KLF5-FLAG (Fig. 2D).…”

Section: 2mentioning

confidence: 99%

“…Like many transcription factors, KLF5 activity is controlled at different levels including DNA dosage [2,3], mRNA transcription [13,14], and several types of protein posttranslational modification [15][16][17]. Our previous studies suggest that the KLF5 protein has a short half-life and is rapidly degraded by the proteasome partially through a ubiquitin-mediated pathway [17].…”

Section: Introductionmentioning

confidence: 99%

Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway

et al. 2007

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KLF5 is a Kruppel-like zinc finger transcription factor modulating cell proliferation, differentiation, cell cycle, apoptosis, and angiogenesis. The KLF5 protein undergoes multiple posttranslational modifications including phosphorylation, acetylation and ubiquitination. We have demonstrated that the KLF5 protein can be ubiquitinated by the WWP1 E3 ubiquitin ligase and degraded by the proteasome. In this study, we found that KLF5 protein degradation is blocked by an N-terminal FLAG tag or a small N-terminal deletion without reducing ubiquitination and degradation mediated by WWP1. Interestingly, the N-terminal fragments of KLF5 containing the first 237 or 171 amino acids are as unstable as the full length KLF5 protein.The N-terminal FLAG tag or 19 amino acid deletion also delayed the degradation of the C-terminal truncated KLF5 proteins. To further understand the mechanism, we generated a lysine-less mutant KLF5(1-171). This mutant is efficiently degraded by the proteasome without ubiquitination in vitro and in vivo. These findings suggest that KLF5 protein degradation by the proteasome could be regulated in a ubiquitin-independent manner.

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KLF5 is frequently deleted and down‐regulated but rarely mutated in prostate cancer

Cited by 126 publications

References 34 publications

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

WW domain-containing E3 ubiquitin protein ligase 1 targets p63 transcription factor for ubiquitin-mediated proteasomal degradation and regulates apoptosis

Krüppel-like factors 4 and 5: the yin and yang regulators of cellular proliferation

Proteasomal degradation of the KLF5 transcription factor through a ubiquitin‐independent pathway

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