MITOGEN-ACTIVATED PROTEIN-KINASE AND MITOGEN-ACTIVATED KINASE PHOSPHATASE-1 EXPRESSION IN THE NOBLE RAT MODEL OF SEX HORMONE-INDUCED PROSTATIC DYSPLASIA AND CARCINOMA

Our recent studies have implicated the TGF-alpha/epidermal growth fact or receptor pathway in the genesis of testosterone (T) and estradiol-1 7 beta (E(2))-induced dysplasia in the dorsolateral prostate (DLP) of Noble rats. This pathway was also found to be markedly up-regulated in the androgen-independent transplantable carcinoma that arose from the DLP of a Noble rat. In the current study, we investigated the express ion of mitogen-activated protein kinase (MAP-kinase) and mitogen-activ ated kinase phosphatase-1 (MKP-1), key downstream regulators of growth factor-activated signal transduction in the DLP of castrated, castrat ed T-supplemented, and T + E(2)-treated rats and in the androgen-indep endent transplantable carcinoma. Both MAP-kinase and MKP-1 expression in the DLP were found to be dependent on androgen stimulation. Immunob lots of DLP from T + E(2)-treated rats demonstrated a selective declin e in MKP-1 levels with no alteration in MAP-kinase expression. These f indings suggest that the dual hormone treatment induces changes in the signal transduction pathway, which favors the protracted mitogenic ac tion of MAP-kinase. In situ hybridization and immunohistochemistry fin dings corroborated the immunoblot data but also revealed that both MAP -kinase and MKP-1 were strongly expressed in severely dysplastic lesio ns, which may indicate the presence of transformed cells in these foci . In this regard, both proteins were strongly expressed in samples of the androgen-independent transplantable carcinoma. Taken together, res ults from this and our recent study suggest that alterations in a grow th factor-MAP-kinase pathway may be important events in the initiation and progression of prostatic carcinoma.