Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells

Richard Hill; Andrew M. Leidal; Patricia A. Madureira; Laura D. Gillis; Haley K. Cochrane; David M. Waisman; Arthur Chiu; Patrick W.K. Lee

doi:10.1016/j.dnarep.2007.10.001

Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells

Richard Hill, Andrew M. Leidal, Patricia A. Madureira, Laura D. Gillis, Haley K. Cochrane, David M. Waisman, Arthur Chiu, Patrick W.K. Lee

Medicine

Medicine

Résultat de recherche: Article › examen par les pairs

25 Citations (Scopus)

Résumé

The cyclin-dependent kinase inhibitor p21^CIP1/WAF1 is a key component in cell cycle control and apoptosis, directing an anti-apoptotic response following DNA damage. Chromium exposure resulted in a 500-1000 fold increase in apoptosis-induced cell death in p21-/- HCT116 cells compared to wild-type or p53-/- cells. p53 shRNA (or transient p53 siRNA) into p21-/- HCT116 cells reduced Cr(VI) sensitivity, suggesting the enhanced apoptosis in p21-/- cells is p53-dependent. Under non-DNA damage conditions, the p53 level in p21-/- cells was significantly higher than in wild-type cells, due to enhanced p53 phosphorylation and stabilization rather than elevated p53 transcription. Wild-type cells showed significant p53 protein induction upon DNA damage whereas p21-/- cells showed no p53 increase. p21-/- cells display the constitutive activation of upstream p53 kinases (ATM, DNA-PK, ATR, AKT and p38). 2D gel analysis revealed p53 patterns in p21-/- cells were distinct from those in wild-type cells before and after chromium exposure. Our results suggest that p21 has an important role in the cellular response to normal replicative stress and its absence leads to a "chronic DNA damage" state that primes the cell for p53-dependent apoptosis.

Langue d'origine	English
Pages (de-à)	239-252
Nombre de pages	14
Journal	DNA Repair
Volume	7
Numéro de publication	2
DOI	https://doi.org/10.1016/j.dnarep.2007.10.001
Statut de publication	Published - févr. 1 2008

Note bibliographique

Funding Information:
This research is supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society. We would like to thank Dr. B. Vogelstein (John Hopkins University, Baltimore, MD) for kindly providing us with our panel of matched HCT116 cell lines (WT, p53−/− and p21−/−).

ASJC Scopus Subject Areas

Biochemistry
Molecular Biology
Cell Biology

ODD de l’ONU

Cette action contribue à la réalisation des objectifs de développement durable suivants

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10.1016/j.dnarep.2007.10.001

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title = "Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells",

abstract = "The cyclin-dependent kinase inhibitor p21CIP1/WAF1 is a key component in cell cycle control and apoptosis, directing an anti-apoptotic response following DNA damage. Chromium exposure resulted in a 500-1000 fold increase in apoptosis-induced cell death in p21-/- HCT116 cells compared to wild-type or p53-/- cells. p53 shRNA (or transient p53 siRNA) into p21-/- HCT116 cells reduced Cr(VI) sensitivity, suggesting the enhanced apoptosis in p21-/- cells is p53-dependent. Under non-DNA damage conditions, the p53 level in p21-/- cells was significantly higher than in wild-type cells, due to enhanced p53 phosphorylation and stabilization rather than elevated p53 transcription. Wild-type cells showed significant p53 protein induction upon DNA damage whereas p21-/- cells showed no p53 increase. p21-/- cells display the constitutive activation of upstream p53 kinases (ATM, DNA-PK, ATR, AKT and p38). 2D gel analysis revealed p53 patterns in p21-/- cells were distinct from those in wild-type cells before and after chromium exposure. Our results suggest that p21 has an important role in the cellular response to normal replicative stress and its absence leads to a {"}chronic DNA damage{"} state that primes the cell for p53-dependent apoptosis.",

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note = "Funding Information: This research is supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society. We would like to thank Dr. B. Vogelstein (John Hopkins University, Baltimore, MD) for kindly providing us with our panel of matched HCT116 cell lines (WT, p53−/− and p21−/−). ",

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AU - Gillis, Laura D.

AU - Cochrane, Haley K.

AU - Waisman, David M.

AU - Chiu, Arthur

AU - Lee, Patrick W.K.

N1 - Funding Information: This research is supported by the National Cancer Institute of Canada with funds from the Canadian Cancer Society. We would like to thank Dr. B. Vogelstein (John Hopkins University, Baltimore, MD) for kindly providing us with our panel of matched HCT116 cell lines (WT, p53−/− and p21−/−).

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AB - The cyclin-dependent kinase inhibitor p21CIP1/WAF1 is a key component in cell cycle control and apoptosis, directing an anti-apoptotic response following DNA damage. Chromium exposure resulted in a 500-1000 fold increase in apoptosis-induced cell death in p21-/- HCT116 cells compared to wild-type or p53-/- cells. p53 shRNA (or transient p53 siRNA) into p21-/- HCT116 cells reduced Cr(VI) sensitivity, suggesting the enhanced apoptosis in p21-/- cells is p53-dependent. Under non-DNA damage conditions, the p53 level in p21-/- cells was significantly higher than in wild-type cells, due to enhanced p53 phosphorylation and stabilization rather than elevated p53 transcription. Wild-type cells showed significant p53 protein induction upon DNA damage whereas p21-/- cells showed no p53 increase. p21-/- cells display the constitutive activation of upstream p53 kinases (ATM, DNA-PK, ATR, AKT and p38). 2D gel analysis revealed p53 patterns in p21-/- cells were distinct from those in wild-type cells before and after chromium exposure. Our results suggest that p21 has an important role in the cellular response to normal replicative stress and its absence leads to a "chronic DNA damage" state that primes the cell for p53-dependent apoptosis.

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Hypersensitivity to chromium-induced DNA damage correlates with constitutive deregulation of upstream p53 kinases in p21-/- HCT116 colon cancer cells

Résumé

Note bibliographique

ASJC Scopus Subject Areas

ODD de l’ONU

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