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J. Biol. Chem., Vol. 280, Issue 6, 4825-4833, February 11, 2005

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Transcriptional Repression of Protein Kinase C via Sp1 by Wild Type p53 Is Involved in Inhibition of Multidrug Resistance 1 P-Glycoprotein Phosphorylation^*

Maocheng Zhan, Dihua Yu, Juehui Liu, Jonathan Hannay, and Raphael E. Pollock

From the Department of Surgical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

The protein kinase C (PKC) family consists of serine/threonine protein kinases that play important roles in signal transduction, cell proliferation, and tumor formation. Recent studies found that PKCs are commonly overexpressed in human tumors, including soft tissue sarcoma (STS). Overexpression of PKCs contributes to invasion and migration of tumor cells and induction of angiogenesis. PKC can also phosphorylate the multidrug resistance (MDR) gene-encoded P-glycoprotein and induce MDR phenotype. Our previous studies showed that mutation of p53 enhanced STS metastasis and mediated the MDR phenotype. Restoring wild type (WT) p53 in STS cells containing mutant p53 sensitized the cells to chemotherapy. In the present study, we found that PKC protein expression is inhibited by WT p53 partly due to reduced PKC mRNA expression in STS cells, but p53 does not affect PKC mRNA stability. Deletion and mutation analysis of the PKC promoter fused to the luciferase reporter gene identified a Sp1 binding site (-244/-234) in the PKC promoter that is required for p53-mediated inhibition of PKC promoter activity. More importantly, PKC phosphorylates and activates MDR1 P-glycoprotein, whereas inhibition of PKC by p53 leads to decreased MDR1 phosphorylation in STS cells, which sensitizes STS cells to chemotherapeutic agents. These data indicate that WT p53 may resensitize STS to chemotherapeutic agents by reducing MDR1 phosphorylation via transcriptional repression of PKC expression. Thus, molecular-based therapies targeting mutant p53 and PKC may be an effective new strategy to improve chemotherapeutic efficacy in STS.

Received for publication, July 2, 2004 , and in revised form, November 17, 2004.

^* This work was supported in part by NCI, National Institutes of Health (NIH) M. D. Anderson Cancer Center Core Grant CA 16672 and NIH Grants 2R01-CA 67802 (to R. E. P.) and R01-CA 109570 (to D. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence may be addressed: Dept. of Surgical Oncology, Unit 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-3636; Fax: 713-794-4830; E-mail: dyu{at}mdanderson.org. To whom correspondence may be addressed: Dept. of Surgical Oncology, Unit 107, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-792-6928; Fax: 713-563-4637; E-mail: rpollock{at}mdanderson.org.

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