Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo.
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-beta(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-beta(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 LbetaT2 cells, activin C antagonized activin A-mediated activity of an follicle-stimulating hormone-beta promoter. Transgenic mice that overexpress activin-betaC 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-beta(C) antagonized Smad signaling in vivo. Underlying the significance of these findings, human testis, liver, and prostate cancers expressed increased activin-betaC immunoreactivity. This study provides evidence that activin-beta(C) is an antagonist of activin A and supplies an impetus to examine its role in development and disease.
Gold
Elspeth
E
Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Australia.
Jetly
Niti
N
O'Bryan
Moira K
MK
Meachem
Sarah
S
Srinivasan
Deepa
D
Behuria
Supreeti
S
Sanchez-Partida
L Gabriel
LG
Woodruff
Teresa
T
Hedwards
Shelley
S
Wang
Hong
H
McDougall
Helen
H
Casey
Victoria
V
Niranjan
Birunthi
B
Patella
Shane
S
Risbridger
Gail
G
D000818:Animals; D015153:Blotting, Western; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007248:Infertility, Male; D028322:Inhibin-beta Subunits / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051899:Smad2 Protein / Q000378:metabolism; D013736:Testicular Neoplasms / Q000235:genetics / Q000378:metabolism; D046888:Tissue Array Analysis; D014162:Transfection
C504186:INHBC protein, human; D051899:Smad2 Protein; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits