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J. Biol. Chem., Vol. 278, Issue 27, 24594-24599, July 4, 2003

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The Role of p53 Deacetylation in p21^Waf1 Regulation by Laminar Flow^*

Lingfang Zeng , Yingjia Zhang , Shu Chien , Xuan Liu ¶ and John Y.-J. Shyy  ||

From the Division of Biomedical Sciences and the ^¶Department of Biochemistry, University of California, Riverside, California 92521 and the Department of Bioengineering and the Whitaker Institute of Biomedical Engineering, University of California, San Diego, La Jolla, California 92093

Laminar flow arrests vascular endothelial cells at the G₀/G₁ phase with concurrent increase in p53 and p21^Waf1. We investigated the molecular mechanism by which laminar flow activates p53 and p21^Waf1 in endothelial cells. The application of a laminar flow (12 dyn/cm²) increased the deacetylation at Lys-320 and Lys-373 of p53 and the acetylation at Lys-382 in human umbilical vein endothelial cells. Laminar flow increased the activity of histone deacetylase (HDAC) and the association of p53 with HDAC1. Treating human umbilical vein endothelial cells with trichostatin A (TSA), an HDAC inhibitor, abolished the flow-induced p53 deacetylation at Lys-320 and Lys-373. To investigate the role of the HDAC-deacetylated p53 in the flow activation of p21^Waf1, we found that TSA inhibited the activation at both the mRNA and protein levels. Deletion and mutation analyses of the p21^Waf1 promoter revealed that flow activated p21^Waf1 through p53 and TSA abrogated this p53-dependent activation. The expression plasmid encoding the p53 mutant, with Lys-320 and Lys-373 replaced by Arg, increased the activity of the co-transfected p21^Waf1 promoter, which demonstrates that HDAC-deacetylated p53 can transactivate the p21^Waf1 gene. The regulation of the p53-p21^Waf1 pathway by laminar flow was further supported by observations that flow caused an increase of p21^Waf1 level in the wild-type HCT116 (p53^+/+) cells but not in the p53-null HCT116 cells.

Received for publication, February 25, 2003 , and in revised form, April 17, 2003.

^* This work was supported in part by NHLBI, National Institutes of Health Grants HL19454, HL43026, and HL64382 (to S. C.) and HL56707 and HL60789 (to J. S.) and NCI, National Institutes of Health Grant CA75180 (to X. L.). 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.

^|| Established Investigator of the American Heart Association. To whom correspondence should be addressed: Div. of Biomedical Sciences, University of California, Riverside, CA 92521-0121. E-mail: john.shyy{at}ucr.edu.

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