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PMID:17938203

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Citation

Liu, H, Lu, ZG, Miki, Y and Yoshida, K (2007) Protein kinase C delta induces transcription of the TP53 tumor suppressor gene by controlling death-promoting factor Btf in the apoptotic response to DNA damage. Mol. Cell. Biol. 27:8480-91

Abstract

Expression of the TP53 tumor suppressor is tightly controlled for its ability to function as a critical regulator of cell growth, proliferation, and death in response to DNA damage. However, little is known about the mechanisms and contributions of the transcriptional regulation of TP53. Here we report that protein kinase C delta (PKCdelta), a ubiquitously expressed member of the novel subfamily of PKC isoforms, transactivates TP53 expression at the transcriptional level. Reporter assays demonstrated that PKCdelta induces the promoter activity of TP53 through the TP53 core promoter element (CPE-TP53) and that such induction is enhanced in response to DNA damage. The results also demonstrate that, upon exposure to genotoxic stress, PKCdelta activates and interacts with the death-promoting transcription factor Btf to co-occupy CPE-TP53. Inhibition of PKCdelta activity decreases the affinity of Btf for CPE-TP53, thereby reducing TP53 expression at both the mRNA and the protein levels. In concert with these results, we show that disruption of Btf-mediated TP53 gene transcription by RNA interference leads to suppression of TP53-mediated apoptosis following genotoxic stress. These findings provide evidence that activation of TP53 gene transcription by PKCdelta triggers TP53-dependent apoptosis in response to DNA damage.

Links

PubMed PMC2169390 Online version:10.1128/MCB.01126-07

Keywords

Animals; Apoptosis; COS Cells; Cell Line, Tumor; Cercopithecus aethiops; DNA Damage; DNA-Binding Proteins/genetics; DNA-Binding Proteins/metabolism; Down-Regulation; Gene Silencing; Humans; Promoter Regions, Genetic/genetics; Protein Binding; Protein Kinase C-delta/metabolism; Repressor Proteins/genetics; Repressor Proteins/metabolism; Transcription Factors/genetics; Transcription Factors/metabolism; Transcription, Genetic; Transcriptional Activation/genetics; Tumor Suppressor Protein p53/genetics; Tumor Suppressor Proteins/genetics; Tumor Suppressor Proteins/metabolism; Up-Regulation

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:KPCD

involved_in

GO:2001022: positive regulation of response to DNA damage stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9NYF8)
  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:BCLF1

involved_in

GO:0043620: regulation of DNA-templated transcription in response to stress

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:BCLF1

involved_in

GO:2001244: positive regulation of intrinsic apoptotic signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:BCLF1

involved_in

GO:2001022: positive regulation of response to DNA damage stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:BCLF1

involved_in

GO:2000144: positive regulation of DNA-templated transcription, initiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P04637)

Seeded From UniProt

complete

HUMAN:P53

involved_in

GO:0006974: cellular response to DNA damage stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:KPCD

involved_in

GO:2001022: positive regulation of response to DNA damage stimulus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_regulation_target:(UniProtKB:Q9NYF8)
  • has_regulation_target:(UniProtKB:P04637)

Seeded From UniProt

complete

See also

References

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