Activin βC-Subunit Heterodimers Provide a New Mechanism of Regulating Activin Levels in the Prostate

Abstract

Activins are formed by dimerization of beta-subunits and, as members of the TGF-beta superfamily, have diverse roles as potent growth and differentiation factors. As the biological function of the activin C homodimer (betaC-betaC) is unknown, we sought to compare activin A (betaA-betaA), B (betaB-betaB), and C homodimer bioactivities and to investigate the consequences of activin betaC-subunit overexpression in prostate tumor cells. Exogenous activin A and B homodimers inhibited cell growth and activated activin-responsive promoters. In contrast, the activin C homodimer was unable to elicit these responses. We previously showed that the activin betaC-subunit heterodimerized with activin betaA in vitro to form activin AC. Therefore, we hypothesize that the activin betaC-subunit regulates the levels of bioactive activin A by the formation of activin AC heterodimers. To test this hypothesis, we measured activin AC heterodimer production using a novel specific two-site ELISA that we developed for this purpose. In the PC3 human prostate tumor cell line, activin betaC-subunit overexpression increased activin AC heterodimer levels, concomitantly reduced activin A levels, and decreased activin signaling. Overall, these data are consistent with a role for the activin betaC-subunit as a regulatory mechanism to reduce activin A secretion via intracellular heterodimerization.

Inhibin, activin, follistatin and FSH serum levels and testicular production are highly modulated during the first spermatogenic wave in mice

“…While the role of the b C subunit in testis development is uncertain at this time, it has been reported to function as a dominant negative regulator of activin A activity by sequestering the b A subunit to produce the activin AC heterodimer (Mellor et al 2003), and hence local activin A bioavailability may be limited by co-expression of both b C and b A subunits. We have shown that both are present in Sertoli and Leydig cells in immature and adult testes, as well as in spermatocytes and elongating spermatids of the adult mouse.…”

“…The function of the b C subunit is also ambiguous as Inhbc null mice display no overt phenotype. However, transfection studies have shown that the b C subunit forms heterodimers with the b A subunit and thereby suppresses the formation of activin A homodimers, providing an additional pathway for intracellular control over activin A production and bioactivity (Mellor et al 2003). The b C subunit mRNA is expressed in adult human and rat testes (Loveland et al 1996, Gold et al 2004) and b C subunit protein is detectable in the Sertoli and Leydig cells, spermatogonia, primary spermatocytes and elongating spermatids of the adult rat testis (Gold et al 2004).…”

Activins and activin antagonists in hepatocellular carcinoma

“…A specific association of activin βC immunoreactivity with mitotic hepatocytes was observed in regenerating liver after partial hepatectomy [50] . It was shown that activin C does not activate activin A-responsive promoters, and it was suggested that the βC subunit regulates the levels of bioactive activin A via the formation of signalingincompetent activin AC heterodimers in PC3 human prostate cancer cells [79,80] . Data regarding the expression of the βC subunit in human liver tumors are not available yet.…”

Activin A and follistatin during the oestrous cycle and early pregnancy in ewes

“…As a member of the transforming growth factor beta superfamily of growth factors, activin forms from the dimerisation of two b-subunits of inhibin (INHB), with different combinations forming functionally different isoforms (Knight 1996, Mellor et al 2003. Follistatin (FST), a structurally unrelated protein, is known to bind activin to regulate its activity (Walton et al 2012).…”