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MDM2 binding induces a conformational change in p53 that is opposed by heat-shock protein 90 and precedes p53 proteasomal degradation.
p53 protein conformation is an important determinant of its localization and activity. Changes in p53 conformation can be monitored by reactivity with wild-type conformation-specific (pAb-1620) or mutant conformation-specific (pAb-240) p53 antibodies. Wild-type p53 accumulated in a mutant (pAb-240 reactive) form when its proteasome-dependent degradation was blocked during recovery from stress treatment and in cells co-expressing p53 and MDM2. This suggests that conformational change precedes wild-type p53 degradation by the proteasome. MDM2 binding to the p53 N terminus could induce a conformational change in wild-type p53. Interestingly, this conformational change was opposed by heat-shock protein 90 and did not require the MDM2 RING-finger domain and p53 ubiquitination. Finally, ubiquitinated p53 accumulated in a pAb-240 reactive form when p53 degradation was blocked by proteasome inhibition, and a p53-ubiquitin fusion protein displayed a mutant-only conformation in MDM2-null cells. These results support a model in which MDM2 binding induces a conformational change that is opposed by heat-shock protein 90 and precedes p53 ubiquitination. The covalent attachment of ubiquitin may "lock" p53 in a mutant conformation in the absence of MDM2-binding and prior to its degradation by the proteasome.
Authors : Sasaki Mark , Nie Linghu , Maki Carl G ,
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Pathways :
WP1531: Vitamin D synthesis
WP1613: 1,4-Dichlorobenzene degradation
WP1616: ABC transporters
WP1650: Fluorobenzoate degradation
WP1654: gamma-Hexachlorocyclohexane degradation
WP1665: Limonene and pinene degradation
WP1673: Naphthalene and anthracene degradation
WP2292: Chemokine signaling pathway
WP731: Sterol regulatory element binding protein related
WP101: Synthesis and Degradation of Ketone Bodies
WP1015: Synthesis and Degradation of Ketone Bodies
WP1018: Apoptosis
WP1049: G Protein Signaling Pathways
WP1058: Senescence and Autophagy
WP1078: G1 to S cell cycle control
WP1079: Proteasome Degradation
WP1083: Cell cycle
WP1126: Tryptophan metabolism
WP1134: Synthesis and Degradation of Ketone Bodies
WP1137: Apoptosis
WP1165: G Protein Signaling Pathways
WP1174: Senescence and Autophagy
WP1195: G1 to S cell cycle control
WP1196: Proteasome Degradation
WP1200: Cell cycle
Related Genes :
Bibliography :
[17363365] MDM2 binding induces a conformational change in p53 that is opposed by heat-shock protein 90 and precedes p53 proteasomal degradation.
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