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.
Subject(s)
Female , Humans , Actin-Related Protein 2 , Genetics , Metabolism , Activin Receptors, Type II , Genetics , Metabolism , Bone Morphogenetic Protein 7 , Genetics , Metabolism , Bone Morphogenetic Protein Receptors, Type II , Genetics , Metabolism , Breast Neoplasms , Genetics , Metabolism , Cellular Senescence , HeLa Cells , MCF-7 Cells , Neoplasm Proteins , Genetics , Metabolism , Protein Serine-Threonine Kinases , Genetics , Metabolism , Receptor, Transforming Growth Factor-beta Type II , Receptors, Transforming Growth Factor beta , Genetics , Metabolism , Smad3 Protein , Genetics , Metabolism , Telomerase , Genetics , Metabolism , Telomere HomeostasisABSTRACT
The process of aging is mitigated by the maintenance and repair of chromosome ends (telomeres), resulting in extended lifespan. This review examines the molecular mechanisms underlying the actions and regulation of the enzyme telomerase reverse transcriptase (TERT), which functions as the primary mechanism of telomere maintenance and regulates cellular life expectancy. Underpinning increased cell proliferation, telomerase is also a key factor in facilitating cancer cell immortalization. The review focuses on aspects of hormonal regulations of telomerase, and the intracellular pathways that converge to regulate telomerase activity with an emphasis on molecular interactions at protein and gene levels. In addition, the basic structure and function of two key telomerase enzyme components-the catalytic subunit TERT and the template RNA (TERC) are discussed briefly.