Soluble guanylyl cyclase ?1 and p53 cytoplasmic sequestration and down-regulation in prostate cancer.

ABSTRACT: Our laboratory has previously identified soluble guanylyl cyclase ?1 (sGC?1) as a novel androgen-regulated gene essential for prostate cancer cell proliferation. sGC?1 expression is highly elevated in prostate tumors, contrasting with the low expression of sGC?1, with which sGC?1 dimerizes to mediate nitric oxide (NO) signaling. In studying its mechanism of action, we have discovered that sGC?1 can inhibit the transcriptional activity of p53 in prostate cancer cells independent of either classical mediators of NO signaling or the guanylyl cyclase activity of sGC?1. Interestingly, sGC?1 inhibition of p53-regulated gene expression was gene specific, targeting genes involved in apoptosis/cell survival. Consistent with this, overexpression of sGC?1 makes prostate cancer cells more resistant to etoposide, a chemotherapeutic and apoptosis-inducing drug. Immunoprecipitation and immunocytochemistry assays show a physical and direct interaction between sGC?1 and p53 in prostate cancer cells. Interestingly, sGC?1 induces p53 cytoplasmic sequestration, representing a new mechanism of p53 inactivation in prostate cancer. Analysis of prostate tumors has shown a direct expression correlation between sGC?1 and p53. Collectively, these data suggest that sGC?1 regulation of p53 activity is important in prostate cancer biology and may represent an important mechanism of p53 down-regulation in those prostate cancers that express significant levels of p53.

SUBMITTER: Cai C 

PROVIDER: S-EPMC3275164 | biostudies-literature | 2012 Feb

REPOSITORIES: biostudies-literature