TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence

Lucy Cassar; Craig Nicholls; Alex R Pinto; Ruping Chen; Lihui Wang; He Li; Jun-Ping Liu

doi:10.1007/s13238-016-0322-1

TGF-beta receptor mediated telomerase inhibition, telomere shortening and breast cancer cell senescence

Protein Cell. 2017 Jan;8(1):39-54. doi: 10.1007/s13238-016-0322-1. Epub 2016 Sep 30.

Authors

Lucy Cassar¹, Craig Nicholls¹, Alex R Pinto¹, Ruping Chen², Lihui Wang², He Li¹, Jun-Ping Liu^{3

4}

Affiliations

¹ Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia.
² Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, Zhejiang Province, China.
³ Molecular Signaling Laboratory, Department of Immunology, Central Eastern Clinical School, Monash University, Prahran, VIC, 3181, Australia. jun-ping.liu@monash.edu.
⁴ Institute of Aging Research, Hangzhou Normal University School of Medicine, Hangzhou, 311121, Zhejiang Province, China. jun-ping.liu@monash.edu.

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.

Keywords: BMPRII; TGFbeta; breast cancer cells; hTERT; senescence; telomerase; telomeres.

MeSH terms

Actin-Related Protein 2 / genetics
Actin-Related Protein 2 / metabolism*
Activin Receptors, Type II / genetics
Activin Receptors, Type II / metabolism*
Bone Morphogenetic Protein 7 / genetics
Bone Morphogenetic Protein 7 / metabolism*
Bone Morphogenetic Protein Receptors, Type II / genetics
Bone Morphogenetic Protein Receptors, Type II / metabolism
Breast Neoplasms / genetics
Breast Neoplasms / metabolism*
Cellular Senescence*
Female
HeLa Cells
Humans
MCF-7 Cells
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism*
Receptor, Transforming Growth Factor-beta Type II
Receptors, Transforming Growth Factor beta / genetics
Receptors, Transforming Growth Factor beta / metabolism*
Smad3 Protein / genetics
Smad3 Protein / metabolism
Telomerase / genetics
Telomerase / metabolism*
Telomere Homeostasis*

Substances

ACTR2 protein, human
Actin-Related Protein 2
BMP7 protein, human
Bone Morphogenetic Protein 7
Neoplasm Proteins
Receptors, Transforming Growth Factor beta
SMAD3 protein, human
Smad3 Protein
Protein Serine-Threonine Kinases
ACVR2B protein, human
Activin Receptors, Type II
BMPR2 protein, human
Bone Morphogenetic Protein Receptors, Type II
Receptor, Transforming Growth Factor-beta Type II
activin receptor type II-A
TERT protein, human
Telomerase