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

Oncogene volume 22, pages 433–444 (2003)Cite this article

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.

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Acknowledgements

We thank Dr Charles J Sherr for kindly providing the plasmid containing Cdk4. We are very grateful to Denise LaRue and Troy Gor for the excellent technical support. This work was supported by NIH grant AG01228 and the Ellison Medical Foundation. WEW and JWS are coholders of the Southland Financial Corporation Distinguished Chair in Geriatric Research.

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Authors and Affiliations

  1. Hamon Center for Therapeutic Oncology Research, The University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, 75390-8593, TX, USA

    Ruben D Ramirez

  2. Department of Cell Biology, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, 75390-9039, TX, USA

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

  3. Department of Internal Medicine, Dallas Veterans Affairs Medical Center, 4500 South Lancaster Road, Mail Code 151, Dallas, 75216, TX, USA

    Kenia Gandia & Carmela P Morales

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Correspondence to Ruben D Ramirez.

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Ramirez, R., Herbert, BS., Vaughan, M. et al. Bypass of telomere-dependent replicative senescence (M1) upon overexpression of Cdk4 in normal human epithelial cells. Oncogene 22, 433–444 (2003). https://doi.org/10.1038/sj.onc.1206046

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