Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells

Ruben D. Ramirez, Brittney Shea Herbert, Melville B. Vaughan, Ying Zou, Kenia Gandia, Carmela P. Morales, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

Abstract

Many stimuli causing 'stress' or DNA damage in cells can produce phenotypes that overlap with telomere-based replicative senescence. In epithelial systems, the p16/RB pathway may function as a stress senescence-signaling pathway independent of telomere shortening. Overexpressing cyclin-dependent kinase 4 (Cdk4) in human epidermal keratinocytes and human mammary epithelial cells not only prevents the p16INK4a-associated premature growth arrest due to telomere-independent stress (e.g., inadequate culture conditions), but also bypasses the ensuing telomere-dependent senescence (M1). Overexpressed Cdk4 in epithelial cells induces a dramatic upregulation of p16INK4a and milder upregulation of p53 and p21WAF1, which become unresponsive to UV irradiation. Despite the high levels of these checkpoint factors, Cdk4-overexpressing cells divide in an apparently normal regulated fashion, are able to respond to changes in calcium levels, retain the stem cell phenotype, and fully differentiate and stratify. These results suggest that the differentiation pathways in Cdk4-overexpressing cells remain intact.

Original languageEnglish (US)
Pages (from-to)433-444
Number of pages12
JournalOncogene
Volume22
Issue number3
DOIs
StatePublished - Jan 23 2003
Externally publishedYes

Fingerprint

Cyclin-Dependent Kinase 4
Cell Aging
Telomere
Epithelial Cells
Up-Regulation
Telomere Shortening
Phenotype
Keratinocytes
DNA Damage
Breast
Stem Cells
Calcium
Growth

Keywords

  • Ageing
  • Cdk inhibitors
  • Cell cycle
  • Epithelial cells
  • Replicative senescence

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Ramirez, R. D., Herbert, B. S., Vaughan, M. B., Zou, Y., Gandia, K., Morales, C. P., ... Shay, J. W. (2003). Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. Oncogene, 22(3), 433-444. https://doi.org/10.1038/sj.onc.1206046

Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. / Ramirez, Ruben D.; Herbert, Brittney Shea; Vaughan, Melville B.; Zou, Ying; Gandia, Kenia; Morales, Carmela P.; Wright, Woodring E.; Shay, Jerry W.

In: Oncogene, Vol. 22, No. 3, 23.01.2003, p. 433-444.

Research output: Contribution to journalArticle

Ramirez, RD, Herbert, BS, Vaughan, MB, Zou, Y, Gandia, K, Morales, CP, Wright, WE & Shay, JW 2003, 'Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells', Oncogene, vol. 22, no. 3, pp. 433-444. https://doi.org/10.1038/sj.onc.1206046
Ramirez, Ruben D. ; Herbert, Brittney Shea ; Vaughan, Melville B. ; Zou, Ying ; Gandia, Kenia ; Morales, Carmela P. ; Wright, Woodring E. ; Shay, Jerry W. / Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. In: Oncogene. 2003 ; Vol. 22, No. 3. pp. 433-444.
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