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Molecular and Cellular Biology, December 2007, p. 8480-8491, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01126-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Protein Kinase C Induces Transcription of the TP53 Tumor Suppressor Gene by Controlling Death-Promoting Factor Btf in the Apoptotic Response to DNA Damage

Department of Molecular Genetics, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan

Received 25 June 2007/ Returned for modification 20 August 2007/ Accepted 2 October 2007

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 (PKC), a ubiquitously expressed member of the novel subfamily of PKC isoforms, transactivates TP53 expression at the transcriptional level. Reporter assays demonstrated that PKC 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, PKC activates and interacts with the death-promoting transcription factor Btf to co-occupy CPE-TP53. Inhibition of PKC 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 PKC triggers TP53-dependent apoptosis in response to DNA damage.

Published ahead of print on 15 October 2007.