TGF-beta-superfamily signaling systems in ovarian cance

The TGF-beta superfamily is a large group of related protein ligands that regulate many cellular functions including cell proliferation and differentiation. TGF-beta, activin and inhibin are three members of this superfamily that may play a significant role in the regulation of normal and neoplastic ovarian cell function. We hypothesize that these ligands can modulate cell-proliferation responses and can induce a specific signal transduction cascade in a population of epithelial ovarian cancer cell lines. We demonstrate that activin and TGF-beta, which signal through similar signal transduction molecules, have differential effects on cell fate. Activin functions to induce cell cycle arrest through the activation of the Smad signaling cascade and an upregulation of p21, whereas TGF-beta mainly causes responsive cells to undergo apoptosis through an increased activation of Smads, upregulation of p21 and the initiation of apoptotic-specific signals.;Unlike TGF-beta and activin, the signal transduction pathways and gene regulation mechanisms involved in an inhibin-specific signal cascade, are poorly understood. We determined, that inhibin, does not propagate an intracellular signal through Smads. Instead, treatment of ovarian-derived cell lines with inhibin leads to a rapid and transient activation of the mitogen activated protein kinase (MAPK) ERK1/2. Activation of MAPK by inhibin provides a novel mechanism by which inhibin can exert its effect within the ovary and pituitary. We used an inducible inhibin-bigenic mouse model to stimulate the production of elevated systemic inhibin and compared the gene expression profiles of control and experimental animals to identify unique up or down inhibin-regulated genes and proteins. Several potential gene targets were identified using two different gene-array analysis techniques. Furthermore, a proteomic approach using surface enhanced laser desorption ionization time-of-flight mass spectroscopy data was employed to provide new insights into the inhibin-action mechanism.;Taken together, these studies provide new insights into the role of TGF-beta superfamily ligands in ovarian cancer cell function and further our understanding of basic inhibin biology, its signal transduction cascades, mode of action and potential gene targets.