Mdm-2 binding and TAF(II)31 recruitment is regulated by hydrogen bond disruption between the p53 residues Thr18 and Asp21
| Autor: | Motonari Uesugi, Guillermina Lozano, Xiaodong C Cheng, Hua Wang, Amy D. Tabor, Wei Zhang, James R. Jabbur |
|---|---|
| Rok vydání: | 2002 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Threonine Transcriptional Activation Cancer Research Ultraviolet Rays Mutant Molecular Sequence Data Repressor Biology Transactivation Cyclins Proto-Oncogene Proteins Genetics Humans Amino Acid Sequence Phosphorylation Molecular Biology TATA-Binding Protein Associated Factors General transcription factor Hydrogen bond Nuclear Proteins Hydrogen Bonding Proto-Oncogene Proteins c-mdm2 Transfection Cell biology Biochemistry Cell culture Trans-Activators Transcription Factor TFIID Tumor Suppressor Protein p53 DNA Damage |
| Zdroj: | Oncogene. 21(46) |
| ISSN: | 0950-9232 |
| Popis: | 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 p21(Waf1/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 TAF(II)31. However, prior incubation of p53 mutants with Mdm-2 modulated TAF(II)31 interaction with p53, suggesting Mdm-2 blocks the accessibility of p53 to TAF(II)31. 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 TAF(II)31 recruitment. |
| Databáze: | OpenAIRE |
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