Regulation of basal and luminal cell-specific cytokeratin expression in rat accessory sex organs. Evidence for a new class of androgen-repressed genes and insight into their pairwise control

Abstract

Co-expression of cytokeratin (CK) pairs has been found to be associated with specific epithelial cell types whose expressions are developmentally regulated. In the prostate, CK 8 and 18 have been identified as luminal cell-specific markers, and CK 5 and 15 have been identified as basal cell-specific markers. In this study, we report the cloning and sequencing of a full-length CK 8 cDNA (1.9 kilobases) from a rat ventral prostate (VP) cDNA library. Although the open reading frame shares 90% homology with mouse CK 8 sequences, nucleotide comparison revealed that rat CK 8 cDNA comprises a species-specific sequence on both 5' and 3' ends. The steady-state levels of CK 8 mRNA were elevated in VP, seminal vesicle (SV), and liver of a castrated rat but not in the other organs such as the coagulating gland, bladder, and thymus. Unlike the other androgen-repressed genes, elevated CK 8 mRNA levels persisted even after the glandular involution was completed, indicating that CK 8 is a new class of androgen-repressed gene. The regression of CK 8 expression may be androgen receptor-mediated, since androgen but not estrogen administration to castrated hosts repressed the CK 8 mRNA levels, and this effect can be antagonized by the simultaneous administration of an antiandrogen (4-hydroxyflutamide). Immunohistochemical staining of prostatic tissues reveals that the CK 8 filamentous structure is shifted reversibly from a uniform distribution to a predominantly basal surface upon androgen deprivation. We noted that the steady-state levels of CK 8 protein remain rather constant throughout the various hormonal treatment, and the steady-state levels of CK 8 mRNA and the rate of CK 8 protein synthesis are consistently elevated. These results suggest that the turnover rate of CK 8 protein may be elevated in the prostatic epithelium from the castrated host. Similarly, the steady-state levels of CK 15 and 18 mRNA in VP and SV are also repressed in an androgen-dependent manner. These data, taken together, indicate that pairwise control of luminal (and possibly basal) specific cytokeratin gene expression remains intact in both VP and SV tissues and that the levels of CK mRNAs expression are negatively regulated by androgen.