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

Ruth Louise Vinall, Clifford G Tepper, X. B. Shi, L. A. Xue, Regina F Gandour-Edwards, Ralph W deVere White

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

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 (p53R273H) facilitates AI growth in castrated nude mice. In addition, we demonstrate that H2 relaxin is responsible for facilitating p53R273H-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 p53R273H-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.

Original languageEnglish (US)
Pages (from-to)2082-2093
Number of pages12
JournalOncogene
Volume25
Issue number14
DOIs
StatePublished - Mar 30 2006

Keywords

  • Mutant p53
  • Prostate cancer
  • Relaxin

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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