Mitogen-activated protein kinase kinase kinase 1 activates androgen receptor-dependent transcription and apoptosis in prostate cancer

Mitogen-activated protein (MAP) kinases phosphorylate the estrogen receptor and activate transcription from estrogen receptor-regulated genes. Here we examine potential interactions between the MAP kinase cascade and androgen receptor-mediated gene regulation. Specifically, we have studied the biolo gical effects of mitogen-activated protein kinase kinase kinase 1 (MEKK1) e xpression in prostate cancer cells. Our findings demonstrate that expressio n of constitutively active MEKK1 induces apoptosis in androgen receptor-pos itive but not in androgen receptor-negative prostate cancer cells. Reconsti tution of the androgen receptor signaling pathway in androgen receptor-nega tive prostate cancer cells restores MEKK1-induced apoptosis. MEKK1 also sti mulates the transcriptional activity of the androgen receptor in the presen ce or absence of ligand, whereas a dominant negative mutant of MEKK1 impair s activation of the androgen receptor by androgen. These studies demonstrat e an unanticipated link between MEKK1 and hormone receptor signaling and ha ve implications for the molecular basis of hormone-independent prostate can cer growth.