Müllerian inhibiting substance: new perspectives and future directions

MIS, as a differentiate and antiproliferative agent, is precisely regulated, for example, at the transcriptional level by such transacting factors as SRY, and posttranslationally by testosterone. Processing of MIS most likely requires an as yet unknown in vivo protease which probably serves to control cleavage of MIS and hence its activation at specific sites wherein a localized program of cell death is initiated via a receptor mediated event. Progress has been made in understanding the molecular domains of MIS; current efforts are focused on characterizing the wild type MIS receptor as well as cloning and expressing the MIS receptor. We need now to understand how to target and efficiently activate MIS at its projected site of action. We must focus, after structural analysis of its receptor, on elucidating the MIS initiated intracellular signals which result in localized cell inhibition. Understanding of these mechanisms will permit design of antitumor agents and therapeutic strategies. Similarly, understanding regulation of MIS expression may lead to therapeutic induction of expression in those states where depressed expression is associated with tumorigenesis, sexual ambiguity, or infertility.