title: Derepression of hTERT gene expression promotes escape from oncogene-induced cellular senescence.
abstract: Oncogene-induced senescence (OIS) is a critical tumor-suppressing mechanism that restrains cancer progression at premalignant stages, in part by causing telomere dysfunction. Currently it is unknown whether this proliferative arrest presents a stable and therefore irreversible barrier to cancer progression. Here we demonstrate that cells frequently escape OIS induced by oncogenic H-Ras and B-Raf, after a prolonged period in the senescence arrested state. Cells that had escaped senescence displayed high oncogene expression levels, retained functional DNA damage responses, and acquired chromatin changes that promoted c-Myc-dependent expression of the human telomerase reverse transcriptase gene (hTERT). Telomerase was able to resolve existing telomeric DNA damage response foci and suppressed formation of new ones that were generated as a consequence of DNA replication stress and oncogenic signals. Inhibition of MAP kinase signaling, suppressing c-Myc expression, or inhibiting telomerase activity, caused telomere dysfunction and proliferative defects in cells that had escaped senescence, whereas ectopic expression of hTERT facilitated OIS escape. In human early neoplastic skin and breast tissue, hTERT expression was detected in cells that displayed features of senescence, suggesting that reactivation of telomerase expression in senescent cells is an early event during cancer progression in humans. Together, our data demonstrate that cells arrested in OIS retain the potential to escape senescence by mechanisms that involve derepression of hTERT expression.
authors: New Jersey Medical School-Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103;
authors: Priyanka L
authors: PL
authors: Patel
authors: New Jersey Medical School-Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103;
authors: Anitha
authors: A
authors: Suram
authors: Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark, NJ 07103;
authors: Neena
authors: N
authors: Mirani
authors: Nuclear Organization and Oncogenesis Unit, Department of Cell Biology and Infection, Institut Pasteur, 75015 Paris, France; INSERM U993, F-75015 Paris, France;
authors: Oliver
authors: O
authors: Bischof
authors: New Jersey Medical School-Cancer Center, Rutgers Biomedical and Health Sciences, Newark, NJ 07103; Department of Microbiology, Biochemistry, and Molecular Genetics, Rutgers Biomedical and Health Sciences, Rutgers University, Newark, NJ 07103 herbigut@njms.rutgers.edu.
authors: Utz
authors: U
authors: Herbig
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival; D016922:Cellular Senescence; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D015689:Oncogene Protein p21(ras) / Q000235:genetics* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019098:Telomerase / Q000235:genetics* / Q000378:metabolism; D016615:Telomere / Q000737:chemistry / Q000378:metabolism; D059505:Telomere Homeostasis
chemical_list: C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D015689:Oncogene Protein p21(ras)
keywords: TERT; oncogene-induced senescence; senescence escape; telomerase; telomere