title: TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence.
abstract: Human telomerase reverse transcriptase (hTERT) plays a central role in telomere lengthening for continuous cell proliferation, but it remains unclear how extracellular cues regulate telomerase lengthening of telomeres. Here we report that the cytokine bone morphogenetic protein-7 (BMP7) induces the hTERT gene repression in a BMPRII receptor- and Smad3-dependent manner in human breast cancer cells. Chonic exposure of human breast cancer cells to BMP7 results in short telomeres, cell senescence and apoptosis. Mutation of the BMPRII receptor, but not TGFbRII, ACTRIIA or ACTRIIB receptor, inhibits BMP7-induced repression of the hTERT gene promoter activity, leading to increased telomerase activity, lengthened telomeres and continued cell proliferation. Expression of hTERT prevents BMP7-induced breast cancer cell senescence and apoptosis. Thus, our data suggest that BMP7 induces breast cancer cell aging by a mechanism involving BMPRII receptor- and Smad3-mediated repression of the hTERT gene.
authors.affiliation: Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia.
authors.forename: Lucy
authors.initials: L
authors.lastname: Cassar
authors.affiliation: Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Nicholls
authors.affiliation: Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia.
authors.forename: Alex R
authors.initials: AR
authors.lastname: Pinto
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, Zhejiang Province, China.
authors.forename: Ruping
authors.initials: R
authors.lastname: Chen
authors.affiliation: Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, Zhejiang Province, China.
authors.forename: Lihui
authors.initials: L
authors.lastname: Wang
authors.affiliation: Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia.
authors.forename: He
authors.initials: H
authors.lastname: Li
authors.affiliation: Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia. jun-ping.liu@monash.edu.|Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, Zhejiang Province, China. jun-ping.liu@monash.edu.
authors.forename: Jun-Ping
authors.initials: JP
authors.lastname: Liu
mesh_terms: D051377:Actin-Related Protein 2 / Q000235:genetics / Q000378:metabolism*; D030301:Activin Receptors, Type II / Q000235:genetics / Q000378:metabolism*; D055419:Bone Morphogenetic Protein 7 / Q000235:genetics / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D016922:Cellular Senescence; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D059505:Telomere Homeostasis
chemical_list: C495926:ACTR2 protein, human; D051377:Actin-Related Protein 2; C525819:BMP7 protein, human; D055419:Bone Morphogenetic Protein 7; D009363:Neoplasm Proteins; D018125:Receptors, Transforming Growth Factor beta; C497790:SMAD3 protein, human; D051900:Smad3 Protein; D017346:Protein Serine-Threonine Kinases; C579679:ACVR2B protein, human; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II; D000077294:Receptor, Transforming Growth Factor-beta Type II; C425585:activin receptor type II-A; C509186:TERT protein, human; D019098:Telomerase
keywords: BMPRII; TGFbeta; breast cancer cells; hTERT; senescence; telomerase; telomeres