Activin A is a potent growth and differentiation factor whose synthesis and bioactivity are tightly regulated. Both follistatin binding and inhibin subunit heterodimerization block access to the activin receptor and/or receptor activation. We postulated that the activin- C subunit provides another mechanism regulating activin bioactivity. To test our hypothesis, we examined the biological effects of activin C and produced mice that overexpress activin- C . Activin C reduced activin A bioactivity in vitro; in LNCaP cells, activin C abrogated both activin A-induced Smad signaling and growth inhibition, and in LT2 cells, activin C antagonized activin A-mediated activity of an follicle-stimulating hormone- promoter. Transgenic mice that overexpress activin-C exhibited disease in testis, liver, and prostate. Male infertility was caused by both reduced sperm production and impaired sperm motility. The livers of the transgenic mice were enlarged because of an imbalance between hepatocyte proliferation and apoptosis. Transgenic prostates showed evidence of hypertrophy and epithelial cell hyperplasia. Additionally, there was decreased evidence of nuclear Smad-2 localization in the testis, liver, and prostate, indicating that overexpression of activin- C antagonized Smad signaling in vivo. Underlying the significance of these findings, human testis, liver, and prostate cancers expressed increased activin-C immunoreactivity. This study provides evidence that activin- C is an antagonist of activin A and supplies an impetus to examine its role in development and disease.
Of all ligands of the transforming growth factor  superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar -subunit, the secretion of inhibin heterodimers (␣/) or activin homodimers (/) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin ␣-and  B -subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local folliclestimulating hormone  regulation.
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.
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