MITOGEN-ACTIVATED PROTEIN-KINASES AND APOPTOSIS IN PIN

Mitogen-activated protein (MAP) kinases are key elements of the signal ling systems needed to transduce different extracellular messages into cellular responses. At least three parallel MAP kinase pathways have been identified: one, stimulated by serum and growth factors to activa te extracellular signal-regulated protein kinases (ERKs) by dual tyros ine and threonine phosphorylation, triggers cell proliferation or diff erentiation; the other two, induced by a variety of cellular stresses to activate c-jun N-terminal kinases (JNKs) and reactivating kinase (p 38/RK), result in growth arrest and induction of apoptosis. Mitogen-ac tivated protein kinase phosphatases (MKPs) inactivate MAP kinases thro ugh dephosphorylation and, thus, can modulate the MAP kinase pathways. Expression of JNK-1, ERK-1, p38/RK and MKP-1 proteins was investigate d by immunohistochemistry and expression of MKP-1 mRNA by in situ hybr idisation in 50 cases of high-grade prostatic intraepithelial neoplasi a (PIN), thought to represent the precursor of prostate cancer. The fr equency of apoptotic cells was also determined in these cases. Overexp ression of the three MAP kinases and MKP-1 mRNA was found in all cases of high-grade PIN compared with normal prostate. Immunoreactivity for MKP-1 protein was found to be as intense as in normal glands in 30% a nd weaker in 56% of the PIN cases. Fourteen per cent of PIN cases did not stain with MKP-1 antibody. The proportion of apoptosis was signifi cantly higher (P < 0.008) in PIN lesions that did not express MKP-1 pr otein than in those that did. These results are consistent with our pr evious demonstration of preferential inhibition of the apoptosis-relat ed kinases by MKP-1 and further support the contention that MKP-1, eve n in PIN, may shift the balance existing between cell proliferation an d death. When expressed, it may inhibiting those pathways that lead to apoptosis.