A novel gene overexpressed in the prostate of castrated rats: Hormonal regulation, relationship to apoptosis and to acquired prostatic cell androgen independence

We have identified a novel complementary DNA (cDNA) corresponding to a gene overexpressed in the rat ventral prostate after castration. This cDNA disp lays 89.4% identity with 453 bp of a mouse EST and 81.5% identity with 157 bp of a human EST and was named PARM-1 for prostatic androgen-repressed mes sage-1. The complete cDNA is 1187 bp long and codes for a protein of 298 amino acid s that contains four potential glycosylation sites and three half cystinyl residues. The PARM-1 gene was found to be expressed at quite low levels in most rat t issues including those of the urogenital tract. The kinetic of induction of PARM-1 gene in the prostate was highly correlated to the development of ap optosis in the whole organ. Supplementation of castrated animals with andro gens reversed both the process of apoptosis and the overexpression of PARM- 1 gene. Supplementation with estrogens did not result in an increase in the PARM-1 messenger RNA levels when compared with the castration alone. Howev er, the treatment resulted in a more rapid return to intact levels in the c astrated plus estrogen group. When apoptosis of testis and prostate was ind uced in vivo by hypophysectomy, it was found that PARM-1 was only overexpre ssed in the prostate. Therefore, PARM-1 seems to be regulated by androgens only in the prostate. Using in situ hybridization and immunohistological te chniques, we have shown that PARM-1 gene product is found exclusively in th e epithelial cells of involuting prostate. Analysis by flow cytometry of MA T LyLu epithelial cells transiently expressing PARM-1 protein did not allow us to demonstrate a direct effect of PARM-1 gene overexpression on the pro grammed death of the transfected cells. Treatment of MAT LyLu cells by tran sforming growth factor-beta induced apoptosis but had no effect on PARM-1 p roduction. However PARM-1 protein has been detected by Western blotting in various cell lines such as MAT LyLu, MAT Lu, and PIF, which are androgen in dependent. This would suggest that PARM-1 gene product would be a marker fo r acquired androgen-independence of these tumor cells.