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Activin Regulates ßA-Subunit and Activin Receptor Messenger Ribonucleic Acid and Cellular Proliferation in Activin-Responsive Testicular Tumor Cells¹

Reproductive Endocrine Unit and National Center for Infertility Research, Massachusetts General Hospital, Boston, Massachusetts 02114

Address all correspondence and requests for reprints to: Alan Schneyer, Ph.D., Reproductive Endocrine Unit, BHX-5, Massachusetts General Hospital, Boston, Massachusetts 02114. E-mail: schneyer.alan{at}mgh.harvard.edu

Activin, a member of the transforming growth factor-ß superfamily of growth and differentiation factors, has a number of actions in embryonic as well as adult tissues. These actions are mediated via a family of receptors containing two subtypes and at least two members of each subtype. Recent evidence demonstrates that activin-responsive cell lines containing different subsets of these receptors are valuable models for dissecting functional relationships among receptor subtype, signal transduced, and response obtained.

TT cells, derived from a p53^-/-/-inhibin^-/- mouse testicular tumor, respond to activin by proliferating, a response that can be inhibited by follistatin (FS) treatment. Using semiquantitative RT-PCR methods, we characterized steady state messenger RNA (mRNA) levels for the inhibin/activin subunits, FS, and activin receptor subtypes under basal conditions and in the presence of activin or FS. These cells produced ample immunoreactive activin A and FS, necessitating higher treatment doses to observe any modulation of cellular proliferation. Furthermore, in the presence of exogenous activin, mRNA levels for activin receptor type IIA (ACTRIIA) and ßA were significantly and profoundly suppressed. In addition, both ACTR1B and ACTRIIB were detectable and down-regulated by exogenous activin, although not to the degree observed for ACTRIIA and ßA. Finally, activin treatment at the higher doses, which decreased activin receptor mRNA levels, resulted in inhibition of cellular proliferation. Taken together with previous observations, our results support the model that these tumor cells respond to an autocrine activin signal by proliferating, whereas exogenous or excess activin results in down-regulation of activin receptor and activin biosynthesis, suggesting a potential autocrine/paracrine mechanism by which activin can modulate its own signal.

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