Complex functions of mutant <i>p53</i> alleles from human prostate cancer

Shi, Xu; Nesslinger, Nancy J.; Deitch, Arline D.; Gumerlock, Paul H.; White, Ralph W. deVere

doi:10.1002/pros.10072

Cited by 40 publications

(35 citation statements)

References 49 publications

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“…In other cancers, p53 GOF activities include upregulation of c-myc, IGF-1 and EGFR (Deb et al, 1992(Deb et al, , 1994Lanyi et al, 1998). Our ChIP data, combined with data obtained in our previous studies (Shi et al, 2002), show that GOF activity plays a critical role in p53 mutant-mediated AI CaP in our experimental system. Our data point to a connection between the p53 R273H / H2 relaxin signaling pathway and the AR signaling pathway.…”

Section: Discussionsupporting

confidence: 68%

“…GOF often occurs by the aberrant binding of mutant p53 to atypical promoters, for example, MDR-1 and PCNA, resulting in the transcription of genes known to be involved in cancer progression (Roemer, 1999;Nesslinger et al, 2003;Scian et al, 2004). In published in vitro studies, we have demonstrated that of 16 common p53 mutations analysed, 11 showed various GOF growth characteristics when transfected into CaP cell lines (Shi et al, 2002). In addition, we found a direct link between the expression of four of these GOF mutants (G245S, R248W, R273H and R273C) and the occurrence of AI CaP (Nesslinger et al, 2003).…”

Section: Introductionmentioning

confidence: 72%

“…In keeping with our data showing that other p53 mutants express H2 relaxin mRNA but at lower levels than p53 R273H , these other p53 mutants were also able to bind to the H2 relaxin promoter, but not as strongly as p53 R273H . The binding of mutant p53 to novel promoters has been documented in many cancers and is considered a GOF characteristic (van Oijen and Slootweg, 2000;El-Hizawi et al, 2002;Shi et al, 2002;Nesslinger et al, 2003;Scian et al, 2004). In CaP, examples of such p53 GOF activity include upregulation of hTERT, MDR-1 and PCNA, and the ability to grow in soft agar (Chin et al, 1992;Cadwell and Zambetti, 2001;Scian et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

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The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

et al. 2006

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Mutations in p53 occur at a rate of approximately 70% in hormone-refractory prostate cancer (CaP), suggesting that p53 mutations facilitate the progression of CaP to androgen-independent (AI) growth. We have previously reported that transfection of p53 gain of function mutant alleles into LNCaP, an androgen-sensitive cell line, allows for AI growth of LNCaP in vitro. We herein confirm the in vivo relevance of those findings by demonstrating that the R273H p53 mutation (p53 R273H ) facilitates AI growth in castrated nude mice. In addition, we demonstrate that H2 relaxin is responsible for facilitating p53 R273H -mediated AI CaP. H2 relaxin is overexpressed in the LNCaP-R273H subline. Downregulation of H2 relaxin expression results in significant inhibition of AI growth, whereas addition of recombinant human H2 relaxin to parental LNCaP promotes AI growth. Inhibition of AI growth was also achieved by blocking expression of LGR7, the cognate receptor of H2 relaxin. Chromatin immunoprecipitation analysis was used to demonstrate that p53 R273H binds directly to the relaxin promoter, further confirming a role for H2 relaxin signaling in p53 R273H -mediated AI CaP. Lastly, we used a reporter gene assay to demonstrate that H2 relaxin can induce the expression of prostate-specific antigen via an androgen receptor-mediated pathway.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

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The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

et al. 2006

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“…hTERT-immortalized prostate epithelial EP156T cells retained intact wt-p53 activity. 9 The p53 R175H mutation is commonly found in cancer cells including prostate cancer, 10 and it is known to confer an oncogenic GOF activity on a background of wtp53. 4 To investigate the effect of p53 mutation, EP156T cells (at passage 25) were infected with a recombinant retrovirus encoding with either p53 R175H mutant (M cells), dominantnegative p53 peptide GSE56 (G cells) or control vector (C cells) (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

et al. 2010

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A mutation within one allele of the p53 tumor suppressor gene can inactivate the remaining wild-type allele in a dominantnegative manner and in some cases can exert an additional oncogenic activity, known as mutant p53 'gain of function' (GOF). To study the role of p53 mutations in prostate cancer and to discriminate between the dominant-negative effect and the GOF activity of mutant p53, we measured, using microarrays, the expression profiles of three immortalized prostate epithelial cultures expressing wild-type, inactivated p53 or mutated p53. Analysis of these gene expression profiles showed that both inactivated p53 and p53 R175H mutant expression resulted in the upregulation of cell cycle progression genes. A second group, which was upregulated exclusively by mutant p53 R175H , was predominantly enriched in developmental genes. This group of genes included the Twist1, a regulator of metastasis and epithelial-mesenchymal transition (EMT). Twist1 levels were also elevated in metastatic prostate cancer-derived cell line DU145, in immortalized lung fibroblasts and in a subset of lung cancer samples, all in a mutant p53-dependent manner. p53 R175H mutant bearing immortalized epithelial cells showed typical features of EMT, such as higher expression of mesenchymal markers, lower expression of epithelial markers and enhanced invasive properties in vitro. The mechanism by which p53 R175H mutant induces Twist1 expression involves alleviation of the epigenetic repression. Our data suggest that Twist1 expression might be upregulated following p53 mutation in cancer cells.

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“…However, the function of R175H in different cell types is controversial. It is certainly debatable to regard R175H simply as a dominantnegative inhibitor of p53 (Pocard et al, 1996;Coursen et al, 1997;Kremenetskaya et al, 1997;Gurova et al, 2002;Shi et al, 2002). Specifically, R175H is known to induce the cytokine interleukin 6 (IL-6) in different cell systems (Runnebaum et al, 1994;Asschert et al, 1999).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines

et al. 2004

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Current therapy for advanced prostate cancer is mainly based on androgen deprivation, although most patients relapse to androgen-insensitive disease. Several mechanisms contributing to androgen-independent growth including alterations in the structure or expression of the androgen receptor (AR) and its cofactors have been identified. Recent evidence suggests that p53 is involved in androgen signaling. The analysis of the effect of p53 on androgen signaling was performed in 22Rv1 and LNCaP prostate cancer cells that express both p53 and AR. The overexpression of p53 diminished the androgenic response in both cell lines in a reporter gene assay. Conversely, the inhibition of p53 by three different p53 inhibitors, Pifithrin-1a (PFT-1a), an inhibitor of p53-dependent transactivation; MDM2, a regulator of p53 expression; and a dominant-negative N-terminally truncated p53 gene also reduced transactivation of androgen-dependent reporter genes. The inactivation of p53 by PFT-1a decreased AR-protein expression in both 22Rv1 and LNCaP cells. Our findings confirm that the overexpression of wild-type p53 decreases androgen function, whereas p53 expression at physiological levels stabilizes AR signaling. Thus, our findings suggest that there is a balance of AR and p53 expression during the androgendependent growth of prostate cancer, which is obliterated during further progression of the disease.

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Complex functions of mutant p53 alleles from human prostate cancer

Abstract: Different mutant p53 alleles from CaP had different, complex functional profiles. The lack of predictable patterns for these alleles suggest that each mutation may uniquely affect p53 function.

Cited by 40 publications

References 49 publications

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7

Mutant p53R175H upregulates Twist1 expression and promotes epithelial–mesenchymal transition in immortalized prostate cells

Inhibition of p53 function diminishes androgen receptor-mediated signaling in prostate cancer cell lines

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