Activin betaC-subunit heterodimers provide a new mechanism of regulating activin levels in the prostate.
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.
Mellor
Sally L
SL
Monash Institute of Reproduction and Development, Monash University, Melbourne, Victoria 3168, Australia.
Ball
Emma M A
EM
O'Connor
Anne E
AE
Ethier
Jean-François
JF
Cranfield
Mark
M
Schmitt
Jacqueline F
JF
Phillips
David J
DJ
Groome
Nigel P
NP
Risbridger
Gail P
GP
D028341:Activins / Q000378:metabolism*; D000818:Animals; D016466:CHO Cells; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D028322:Inhibin-beta Subunits / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000502:physiology; D011467:Prostate / Q000378:metabolism*; D012680:Sensitivity and Specificity; D014407:Tumor Cells, Cultured
C422402:INHBB protein, human; C504186:INHBC protein, human; C103008:inhibin beta A subunit; D028341:Activins; D028322:Inhibin-beta Subunits