Cascade Induction of c-fos, c-myc, and Heat Shock 70K Transcripts during Regression of the Rat Ventral Prostate Gland

Abstract

Castration of an adult male rat results in the rapid regression of the ventral prostate gland. Most of the acinar epithelial cells lining the ducts of the gland will die during the first 5 days after androgen withdrawal. The molecular events which accompany the death of these cells were studied by examining RNA isolated from ventral prostate glands of normal and from a sequential 24-h series of castrate rats. These RNAs were analyzed by Northern blot methods to quantify the expression of growth-related (c-fos, c-myc, and heat shock 70K) and cell maintenance (atubulin) genes during prostatic regression. Each of these genes showed a bimodal pattern of expression. Within the first few days after castration, transcript levels decline; whereas later, during the most active period of cell death, their expression was transiently induced. Levels of mature c-myc, and α-tubulin transcripts increased approximately 6- to 8-fold on the third day after castration, while transcripts encoding hsp 70-related genes increased greater than 6-fold on the fourth day after castration. Further analysis of RNA extracted from regressing ventral prostate glands at sequential 12-h intervals after castration showed that the c-fos gene was induced at 36 h, earlier than c-myc, α-tubulin, and hsp 70. Intriguingly, even after the initial inductive event, the activity of the c-fos gene continued to fluctuate in a diurnal pattern (transcript levels elevated in the morning and depressed in the evening) during the next 3 days of regression. Subsequent analysis of cHa-ras and cKi-ras expression during regression showed that the mRNA levels for both of these genes exhibited some minor fluctuations, but never reached levels higher than in ventral prostate tissue of intact rats. Quantitative analysis of RNA extracted from an enriched population of rat macrophages or from separated ventral prostate stromal cells of a 4-day castrate rat compared to RNA from prostatic epithelial cells of a 4-day castrate rat showed that the enhanced levels of c-myc and hsp 70 transcripts in the ventral prostate were encoded by the epithelial cells and are not likely to be related to a late phagocytic invasion of the gland. Our results imply that prostatic cell death is accompanied by a sequential pattern of gene activity (c-fos→c-myc→hsp 70) which we have termed a “reactive cascade.” This cascade of gene activity mimics the molecular events which occur during proliferative stimulation of cultured cells, suggesting that these two cellular processes (death and proliferation) may share common signal mechanisms.