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p53 regulates cellular responses to environmental carcinogen benzo[a]pyrene-7,8-diol-9,10-epoxide in human lung cancer cells.

Abstract
The p53 tumor suppressor is a mutational target of environmental carcinogen anti-benzo[a]pyrene-7,8-diol-9,10-epoxide (BPDE). We now demonstrate that p53 plays an important role in regulation of cellular responses to BPDE. Exposure of p53-null H1299 human lung cancer cells to BPDE resulted in S and G(2) phase cell cycle arrest, but not mitotic block, which correlated with induction of cyclin B1 protein expression, down-modulation of cell division cycle 25C (Cdc25C) and Cdc25B protein levels, and hyperphosphorylation of Cdc25C (S216), cyclin-dependent kinase 1 (Cdk1; Y15), checkpoint kinase 1 (Chk1; S317 and S345) and Chk2 (T68). The BPDE-induced S phase block, but not the G(2)/M phase arrest, was significantly attenuated by knockdown of Chk1 protein level. The BPDE-mediated accumulation of sub-diploid fraction (apoptotic cells) was significantly decreased in H1299 cells transiently transfected with both Chk1 and Chk2 specific siRNAs. The H460 human lung cancer cell line (wild-type p53) was relatively more sensitive to BPDE-mediated growth inhibition and enrichment of sub-diploid apoptotic fraction compared with H1299 cells. The BPDE exposure failed to activate either S or G(2) phase checkpoint in H460 cells. Instead, the BPDE-treated H460 cells exhibited a nearly 8-fold increase in sub-diploid apoptotic cells that was accompanied by phosphorylation of p53 at multiple sites. Knockdown of p53 protein level in H460 cells attenuated BPDE-induced apoptosis but enforced activation of S and G(2) phase checkpoints. In conclusion, the present study points towards an important role of p53 in regulation of cellular responses to BPDE in human lung cancer cells.
AuthorsHui Xiao, Shivendra V Singh
JournalCell cycle (Georgetown, Tex.) (Cell Cycle) Vol. 6 Issue 14 Pg. 1753-61 (Jul 15 2007) ISSN: 1551-4005 [Electronic] United States
PMID17630511 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Carcinogens, Environmental
  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Epoxy Compounds
  • Tumor Suppressor Protein p53
  • Tumor Suppressor Proteins
  • Benzo(a)pyrene
  • Protein Kinases
  • Checkpoint Kinase 2
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Protein Serine-Threonine Kinases
Topics
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Benzo(a)pyrene (pharmacology)
  • Carcinogens, Environmental (pharmacology)
  • Cell Cycle (drug effects, physiology)
  • Cell Cycle Proteins (genetics, metabolism)
  • Cell Line, Tumor
  • Checkpoint Kinase 1
  • Checkpoint Kinase 2
  • DNA-Binding Proteins (genetics, metabolism)
  • Enzyme Activation
  • Epoxy Compounds (metabolism)
  • Humans
  • Lung Neoplasms (metabolism)
  • Protein Kinases (genetics, metabolism)
  • Protein Serine-Threonine Kinases (genetics, metabolism)
  • RNA Interference
  • Tumor Suppressor Protein p53 (genetics, metabolism)
  • Tumor Suppressor Proteins (genetics, metabolism)

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