title: Activin C antagonizes activin A in vitro and overexpression leads to pathologies in vivo.
abstract: 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.
authors.affiliation: Centre for Urological Research, Monash Institute of Medical Research, Monash University, Clayton, Australia.
authors.forename: Elspeth
authors.initials: E
authors.lastname: Gold
authors.forename: Niti
authors.initials: N
authors.lastname: Jetly
authors.forename: Moira K
authors.initials: MK
authors.lastname: O'Bryan
authors.forename: Sarah
authors.initials: S
authors.lastname: Meachem
authors.forename: Deepa
authors.initials: D
authors.lastname: Srinivasan
authors.forename: Supreeti
authors.initials: S
authors.lastname: Behuria
authors.forename: L Gabriel
authors.initials: LG
authors.lastname: Sanchez-Partida
authors.forename: Teresa
authors.initials: T
authors.lastname: Woodruff
authors.forename: Shelley
authors.initials: S
authors.lastname: Hedwards
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.forename: Helen
authors.initials: H
authors.lastname: McDougall
authors.forename: Victoria
authors.initials: V
authors.lastname: Casey
authors.forename: Birunthi
authors.initials: B
authors.lastname: Niranjan
authors.forename: Shane
authors.initials: S
authors.lastname: Patella
authors.forename: Gail
authors.initials: G
authors.lastname: Risbridger
mesh_terms: 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
chemical_list: C504186:INHBC protein, human; D051899:Smad2 Protein; C103008:inhibin beta A subunit; D028322:Inhibin-beta Subunits