Early gene expression during androgen-induced inhibition of proliferation of prostate cancer cells: a new suppressor candidate on chromosome 13, in the BRCA2-Rb1 locus.

In the prostate gland cell numbers are regulated by androgens through three separate pathways: (a) inhibition of cell death (apoptosis), (b) induction of cell proliferation (step 1), and (c) inhibition of cell proliferation (step 2, proliferative shutoff). The precise regulation of these control pathways is still elusive. The human prostate carcinoma LNCaP cell line variants express a subset of proliferative pathways comparable to those present in normal prostate cells (LNCaP-FGC expresses both steps, LNCaP-LNO expresses step 2, LNCaP-TAC expresses step 1, LNCaP-TJA expresses neither). The purpose of the present work is to identify the genes involved in the androgen-induced proliferative arrest of these cells. Using a Wang-Brown subtracted library, a set of shutoff specific genes has been isolated. One of these new genes, AS3, shows high expression in the early regulatory phase of androgen-induced proliferative shutoff in the cell variants and in the prostates of castrated rats. The putative 1391-residue polypeptide has the molecular size of about 186 kDa. It has coiled-coil structures that usually participate in protein-protein interactions, a perfect leucine-zipper that suggests DNA binding, nuclear localization motifs, proline- and serinerich domains, unique C-terminal acidic-basic repeats, and ATP- and DNA-binding motifs. The transcript has 34 exons in a 200,000 bp region on chromosome 13q12-q13, downstream of the breast cancer susceptibility gene BRCA2, and centromeric to the retinoblastoma (Rb1) locus. This area is subject to frequent allelic losses in cancers, and is believed to carry a number of cryptic suppressor genes. The AS3 gene seems to be a novel candidate in the regulation of androgen-induced proliferative arrest of human prostate cells.