The p53/p21WAF/CIP Pathway Mediates Oxidative Stress and Senescence in Dyskeratosis Congenita Cells with Telomerase Insufficiency

Erik R Westin; Nukhet Aykin-Burns; Erin M Buckingham; Douglas R Spitz; Frederick D Goldman; Aloysius J Klingelhutz

doi:10.1089/ars.2010.3444

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The p53/p21WAF/CIP Pathway Mediates Oxidative Stress and Senescence in Dyskeratosis Congenita Cells with Telomerase Insufficiency

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The p53/p21WAF/CIP Pathway Mediates Oxidative Stress and Senescence in Dyskeratosis Congenita Cells with Telomerase Insufficiency

Erik R Westin, Nukhet Aykin-Burns, Erin M Buckingham, Douglas R Spitz, Frederick D Goldman and Aloysius J Klingelhutz

Antioxidants & redox signaling, Vol.14(6), pp.985-997

03/15/2011

DOI: 10.1089/ars.2010.3444

PMCID: PMC3043957

PMID: 21087144

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Abstract

Telomere attrition is a natural process that occurs due to inadequate telomere maintenance. Once at a critically short threshold, telomeres signal growth arrest, leading to senescence. Telomeres can be elongated by the enzyme telomerase, which adds de novo telomere repeats to the ends of chromosomes. Mutations in genes for telomere binding proteins or components of telomerase give rise to the premature aging disorder dyskeratosis congenita (DC), which is characterized by extremely short telomeres and an aging phenotype. The current study demonstrates that DC cells signal a DNA damage response through p53 and its downstream mediator, p21 WAF/CIP , which is accompanied by an elevation in steady-state levels of superoxide and percent glutathione disulfide, both indicators of oxidative stress. Poor proliferation of DC cells can be partially overcome by reducing O 2 tension from 21% to 4%. Further, restoring telomerase activity or inhibiting p53 or p21 WAF/CIP significantly mitigated growth inhibition as well as caused a significant decrease in steady-state levels of superoxide. Our results support a model in which telomerase insufficiency in DC leads to p21 WAF/CIP signaling, via p53, to cause increased steady-state levels of superoxide, metabolic oxidative stress, and senescence. Antioxid. Redox Signal. 14, 985–997.

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Title: Subtitle: The p53/p21WAF/CIP Pathway Mediates Oxidative Stress and Senescence in Dyskeratosis Congenita Cells with Telomerase Insufficiency
Creators: Erik R Westin - 1Interdisciplinary Program in Genetics, University of Iowa, Iowa City, Iowa
Nukhet Aykin-Burns - 2Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Erin M Buckingham - 3Department of Microbiology, University of Iowa, Iowa City, Iowa
Douglas R Spitz - 2Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
Frederick D Goldman - 4Department of Pediatrics, University of Alabama, Birmingham, Alabama
Aloysius J Klingelhutz - 3Department of Microbiology, University of Iowa, Iowa City, Iowa
Resource Type: Journal article
Publication Details: Antioxidants & redox signaling, Vol.14(6), pp.985-997
DOI: 10.1089/ars.2010.3444
PMID: 21087144
PMCID: PMC3043957
NLM abbreviation: Antioxid Redox Signal
ISSN: 1523-0864
eISSN: 1557-7716
Publisher: Mary Ann Liebert, Inc
Language: English
Date published: 03/15/2011
Academic Unit: Microbiology and Immunology; Stead Family Department of Pediatrics; Pathology; Radiation Oncology
Record Identifier: 9984001205502771

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