title: Stem cell antigen-1 enhances tumorigenicity by disruption of growth differentiation factor-10 (GDF10)-dependent TGF-beta signaling.
abstract: Stem cell antigen (Sca)-1/Ly6A, a glycerophosphatidylinositol-linked surface protein, was found to be associated with murine stem cell- and progenitor cell-enriched populations, and also has been linked to the capacity of tumor-initiating cells. Despite these interesting associations, this protein's functional role in these processes remains largely unknown. To identify the mechanism underlying the protein's possible role in mammary tumorigenesis, Sca-1 expression was examined in Sca-1(+/EGFP) mice during carcinogenesis. Mammary tumor cells derived from these mice readily engrafted in syngeneic mice, and tumor growth was markedly inhibited on down-regulation of Sca-1 expression. The latter effect was associated with significantly elevated expression of the TGF-β ligand growth differentiation factor-10 (GDF10), which was found to selectively activate TGF-β receptor (TβRI/II)-dependent Smad3 phosphorylation. Overexpression of GDF10 attenuated tumor formation; conversely, silencing of GDF10 expression reversed these effects. Sca-1 attenuated GDF10-dependent TGF-β signaling by disrupting the heterodimerization of TβRI and TβRII receptors. These findings suggest a new functional role for Sca-1 in maintaining tumorigenicity, in part by acting as a potent suppressor of TGF-β signaling.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
authors.forename: Geeta
authors.initials: G
authors.lastname: Upadhyay
authors.forename: Yuzhi
authors.initials: Y
authors.lastname: Yin
authors.forename: Hongyan
authors.initials: H
authors.lastname: Yuan
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Rik
authors.initials: R
authors.lastname: Derynck
authors.forename: Robert I
authors.initials: RI
authors.lastname: Glazer
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000235:genetics; D055413:Growth Differentiation Factor 10 / Q000235:genetics* / Q000378:metabolism*; D008325:Mammary Neoplasms, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D051900:Smad3 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000950:Antigens, Ly; C525784:Gdf10 protein, mouse; D055413:Growth Differentiation Factor 10; C074650:Ly6a protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D018125:Receptors, Transforming Growth Factor beta; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II