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Mdm-2 binding and TAFII31 recruitment is regulated by hydrogen bond disruption between the p53 residues Thr18 and Asp21

Oncogene volume 21, pages 7100–7113 (2002)Cite this article

Abstract

Analyses of five wild-type p53 containing cell lines revealed lineage specific differences in phosphorylation of Thr18 after treatment with ionizing (IR) or ultraviolet (UV) radiation. Importantly, Thr18 phosphorylation correlated with induction of the p53 downstream targets p21Waf1/Cip1 (p21) and Mdm-2, suggesting a transactivation enhancing role. Thr18 phosphorylation has been shown to abolish side-chain hydrogen bonding between Thr18 and Asp21, an interaction necessary for stabilizing alpha–helical conformation within the transactivation domain. Mutagenesis-derived hydrogen bond disruption attenuated the interaction of p53 with the transactivation repressor Mdm-2 but had no direct effect on the interaction of p53 with the basal transcription factor TAFII31. However, prior incubation of p53 mutants with Mdm-2 modulated TAFII31 interaction with p53, suggesting Mdm-2 blocks the accessibility of p53 to TAFII31. Consistently, p53-null cells transfected with hydrogen bond disrupting p53 mutants demonstrated enhanced endogenous p21 expression, whereas p53/Mdm-2-double null cells exhibited no discernible differences in p21 expression. We conclude disruption of intramolecular hydrogen bonding between Thr18 and Asp21 enhances p53 transactivation by modulating Mdm-2 binding, facilitating TAFII31 recruitment.

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Acknowledgements

We thank Jason Grier and Lisa Amelse, and Drs Mini Kapoor, Peng Huang, Michele Sawadogo, Paul Chiao, John McMurray, Ralph Arlinghaus and Yanping Zhang for their helpful assistance and discussion. This work was supported in part by NIH grant CA67987. JR Jabbur was a recipient of the American Legion Auxiliary Fellowship.

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Authors and Affiliations

  1. Department of Pathology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    James R Jabbur, Amy D Tabor, Hua Wang & Wei Zhang

  2. Department of Molecular Genetics, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Hua Wang & Guillermina Lozano

  3. Cancer Genomics Laboratory, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    James R Jabbur, Amy D Tabor, Hua Wang & Wei Zhang

  4. Graduate Program in Cancer Biology, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    James R Jabbur, Guillermina Lozano & Wei Zhang

  5. Graduate Program in Genes and Development, The University of Texas M.D. Anderson Cancer Center, Houston, 77030, Texas, TX, USA

    Hua Wang

  6. Sealy Center for Structural Biology and the Department of Pharmacology and Toxicology, The University of Texas Medical Branch at Galveston, Galveston, 77555, Texas, TX, USA

    Xiaodong Cheng

  7. Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, 77030, Texas, TX, USA

    Motonari Uesugi

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Correspondence to Wei Zhang.

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Jabbur, J., Tabor, A., Cheng, X. et al. Mdm-2 binding and TAFII31 recruitment is regulated by hydrogen bond disruption between the p53 residues Thr18 and Asp21. Oncogene 21, 7100–7113 (2002). https://doi.org/10.1038/sj.onc.1205856

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