The R273H p53 mutation can facilitate the androgen-independent growth of LNCaP by a mechanism that involves H2 relaxin and its cognate receptor LGR7
| Autor: | Xu-Bao Shi, Regina F Gandour-Edwards, Clifford G. Tepper, R. W. De Vere White, Lingru Xue, Ruth Louise Vinall |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Male
Cancer Research Mice Nude Enzyme-Linked Immunosorbent Assay Biology medicine.disease_cause Cell Line Receptors G-Protein-Coupled Mice Downregulation and upregulation LNCaP Genetics medicine Animals Humans RNA Messenger Receptor Promoter Regions Genetic Molecular Biology DNA Primers Oligonucleotide Array Sequence Analysis Relaxin Reporter gene Base Sequence urogenital system Transfection Genes p53 Recombinant Proteins Cell biology Culture Media Conditioned Mutation Cancer research Androgens RNA Interference Carcinogenesis Chromatin immunoprecipitation hormones hormone substitutes and hormone antagonists Cell Division |
| Zdroj: | Oncogene. 25(14) |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|