TY - JOUR
T1 - Activin βC-subunit heterodimers provide a new mechanism of regulating activin levels in the prostate
AU - Mellor, Sally L.
AU - Ball, Emma M A
AU - O'Connor, Anne E.
AU - Ethier, Jean François
AU - Cranfield, Mark
AU - Schmitt, Jacqueline F.
AU - Phillips, David J.
AU - Groome, Nigel P.
AU - Risbridger, Gail P.
PY - 2003/10/1
Y1 - 2003/10/1
N2 - Activins are formed by dimerization of β-subunits and, as members of the TGF-β superfamily, have diverse roles as potent growth and differentiation factors. As the biological function of the activin C homodimer (βC-βC) is unknown, we sought to compare activin A (βA-βA), B (βB-β B), and C homodimer bioactivities and to investigate the consequences of activin βC-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 βC-subunit heterodimerized with activin βA in vitro to form activin AC. Therefore, we hypothesize that the activin β C-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 βC-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 β C-subunit as a regulatory mechanism to reduce activin A secretion via intracellular heterodimerization.
AB - Activins are formed by dimerization of β-subunits and, as members of the TGF-β superfamily, have diverse roles as potent growth and differentiation factors. As the biological function of the activin C homodimer (βC-βC) is unknown, we sought to compare activin A (βA-βA), B (βB-β B), and C homodimer bioactivities and to investigate the consequences of activin βC-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 βC-subunit heterodimerized with activin βA in vitro to form activin AC. Therefore, we hypothesize that the activin β C-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 βC-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 β C-subunit as a regulatory mechanism to reduce activin A secretion via intracellular heterodimerization.
UR - http://www.scopus.com/inward/record.url?scp=0141785441&partnerID=8YFLogxK
U2 - 10.1210/en.2003-0225
DO - 10.1210/en.2003-0225
M3 - Article
C2 - 12960042
AN - SCOPUS:0141785441
SN - 0013-7227
VL - 144
SP - 4410
EP - 4419
JO - Endocrinology
JF - Endocrinology
IS - 10
ER -