Abstract
Mutation of four lysine residues in the p53 C-terminal domain inhibits MDM2-dependent ubiquitination of p53 and alters its subcellular distribution. This implies that modification (such as acetylation and phosphorylation) of amino acid residues in p53 C-terminal domain, regulate the biological functions of p53. In this study, we demonstrated that p53 with lysine residues 372, 373, 381, and 382 mutated to alanine (the A4 mutant) retained the transactivation activity of wild-type p53, although the transactivation activity of p21 promoter by the A4 mutant was slightly reduced. The inducible expression of wild-type p53 and the A4 mutant in H1299 cells caused growth inhibition due to cell-cycle arrest. Consistent with previous studies, the expression of wild-type p53 elicited G1 and G2 arrests. However, the cells expressing the A4 mutant underwent G1 arrest but not G2 arrest. Cyclin B1-associated kinase activity was reduced in cells expressing wild-type p53 but not A4, when the cells underwent G2 arrest. This suggests that modification of the p53 C-terminal domain might inhibit p53-mediated G2 arrest. In other words, p53 requires an intact C-terminus to induce G2 arrest.
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Acknowledgements
We thank Marjorie Johnson for her technical assistance, Maureen Goode, PhD (Scientific Publications Dept.) for editing assistance, and Carmelita Concepcion and Peggy James for preparation of this manuscript. This work was partially supported by grants from the National Cancer Institute and the National Institutes of Health (P01 CA78778-01A1) [JA Roth]; SPORE (2P50-CA70970-04); a developmental grant from the NCI for the University of Texas M. D. Anderson Cancer Center SPORE (P50-CA70907) in lung cancer (T Mukhopadhyay); by gifts to the Division of Surgery from Tenneco and Exxon for the Core Laboratory Facility; by the UT M. D. Anderson Cancer Center Support Core Grant (CA 16672); by a grant from the Tobacco Settlement Funds as appropriated by the Texas State Legislature (Project 8); the W. M. Keck Foundation; and a sponsored research agreement with Introgen Therapeutics, Inc. (SR93-004-1).
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