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

doi:10.1038/sj.onc.1206046

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 journal › Article › peer-review

68 Scopus citations

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 p16^INK4a-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 p16^INK4a and milder upregulation of p53 and p21^WAF1, 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 language	English (US)
Pages (from-to)	433-444
Number of pages	12
Journal	Oncogene
Volume	22
Issue number	3
DOIs	https://doi.org/10.1038/sj.onc.1206046
State	Published - Jan 23 2003
Externally published	Yes

Keywords

Ageing
Cdk inhibitors
Cell cycle
Epithelial cells
Replicative senescence

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

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10.1038/sj.onc.1206046

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

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

note = "Funding Information: 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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AU - Zou, Ying

AU - Gandia, Kenia

AU - Morales, Carmela P.

AU - Wright, Woodring E.

AU - Shay, Jerry W.

N1 - Funding Information: 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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N2 - 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.

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

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