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

Producción científica: Contribución a una revista › Artículo › revisión exhaustiva

25 Citas (Scopus)

Resumen

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.

Idioma original	English
Páginas (desde-hasta)	239-252
Número de páginas	14
Publicación	DNA Repair
Volumen	7
N.º	2
DOI	https://doi.org/10.1016/j.dnarep.2007.10.001
Estado	Published - feb. 1 2008

Nota bibliográfica

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

ODS de las Naciones Unidas

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10.1016/j.dnarep.2007.10.001

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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 - Cochrane, Haley K.

AU - Waisman, David M.

AU - Chiu, Arthur

AU - Lee, Patrick W.K.

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

Resumen

Nota bibliográfica

ASJC Scopus Subject Areas

ODS de las Naciones Unidas

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