235. Activin C antagonises activin A in vitro and over-expression leads to prostate pathologies in vivo

Activin A is a well characterised inhibitor of proliferation in most epithelial cells. The actions of activin A on cell growth are mediated through Smad-dependent pathways. Activin A is potent at low levels, therefore its synthesis and bioactivity must be tightly regulated. Follistatin binding or inhibin subunit heterodimerisation block access to the activin receptor and/or receptor activation. We postulate that another mechanism of regulating activin A bioactivity is through the activin-βC subunit. In order to test our hypothesis produced recombinant activin C and mice overexpressing activin-βC. Recombinant activin C abrogated activin A-induced growth inhibition in vitro and the mechanism of action was downregulation of activin A-induced Smad signalling molecules. In the prostate overexpression of activin-βC increased epithelial cell proliferation while there was no significant difference in apoptotic epithelial cells. This imbalance between proliferation and apoptosis led to a significant increase in ventral prostate weight, prostatic hypertrophy and epithelial cell hyperplasia. A significant decrease in nuclear localisation of Smad-2 was associated with activin-βC overexpression in the prostate which implies antagonism of activin signalling also occurs in vivo. This is the first study to provide evidence that activin-βC is an antagonist of activin A in vitro and in vivo and implicates a role for the activin-βC subunit in maintenance of tissue homeostasis in the prostate.