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Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation.

ABSTRACT: The transcriptional activity of p53 is regulated by a cascade of posttranslational modifications. Although acetylation of p53 by CREB-binding protein (CBP)/p300 is known to be indispensable for p53 activation, the role of phosphorylation, and in particular multisite phosphorylation, in activation of CBP/p300-dependent p53 transcriptional pathways remains unclear. We investigated the role of single site and multiple site phosphorylation of the p53 transactivation domain in mediating its interaction with CBP and with the ubiquitin ligase HDM2. Phosphorylation at Thr18 functions as an on/off switch to regulate binding to the N-terminal domain of HDM2. In contrast, binding to CBP is modulated by the extent of p53 phosphorylation; addition of successive phosphoryl groups enhances the affinity for the TAZ1, TAZ2, and KIX domains of CBP in an additive manner. Activation of p53-dependent transcriptional pathways requires that p53 compete with numerous cellular transcription factors for binding to limiting amounts of CBP/p300. Multisite phosphorylation represents a mechanism for a graded p53 response, with each successive phosphorylation event resulting in increasingly efficient recruitment of CBP/p300 to p53-regulated transcriptional programs, in the face of competition from cellular transcription factors. Multisite phosphorylation thus acts as a rheostat to enhance binding to CBP/p300 and provides a plausible mechanistic explanation for the gradually increasing p53 response observed following prolonged or severe genotoxic stress.

SUBMITTER: Lee CW

PROVIDER: S-EPMC2984141 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation.

Lee Chul Won CW Ferreon Josephine C JC Ferreon Allan Chris M AC Arai Munehito M Wright Peter E PE

Proceedings of the National Academy of Sciences of the United States of America 20101020 45

The transcriptional activity of p53 is regulated by a cascade of posttranslational modifications. Although acetylation of p53 by CREB-binding protein (CBP)/p300 is known to be indispensable for p53 activation, the role of phosphorylation, and in particular multisite phosphorylation, in activation of CBP/p300-dependent p53 transcriptional pathways remains unclear. We investigated the role of single site and multiple site phosphorylation of the p53 transactivation domain in mediating its interacti ...[more]

PMID: 20962272

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Project description:The progressive neurodegenerative disorder Alzheimer's disease (AD) manifests as loss of cognitive functions, and finally leads to death of the affected individual. AD may result from accumulation of amyloid plaques. These amyloid plaques comprising of amyloid-beta 42 (A?42) polypeptides results from the improper cleavage of amyloid precursor protein (APP) in the brain. The A?42 plaques have been shown to disrupt the normal cellular processes and thereby trigger abnormal signaling which results in the death of neurons. However, the molecular-genetic mechanism(s) responsible for A?42 mediated neurodegeneration is yet to be fully understood.We have utilized Gal4/UAS system to develop a transgenic fruit fly model for A?42 mediated neurodegeneration. Targeted misexpression of human A?42 in the differentiating photoreceptor neurons of the developing eye of transgenic fly triggers neurodegeneration. This progressive neurodegenerative phenotype resembles Alzheimer's like neuropathology. We identified a histone acetylase, CREB Binding Protein (CBP), as a genetic modifier of A?42 mediated neurodegeneration. Targeted misexpression of CBP along with A?42 in the differentiating retina can significantly rescue neurodegeneration. We found that gain-of-function of CBP rescues A?42 mediated neurodegeneration by blocking cell death. Misexpression of A?42 affects the targeting of axons from retina to the brain but misexpression of full length CBP along with A?42 can restore this defect. The CBP protein has multiple domains and is known to interact with many different proteins. Our structure function analysis using truncated constructs lacking one or more domains of CBP protein, in transgenic flies revealed that Bromo, HAT and polyglutamine (BHQ) domains together are required for the neuroprotective function of CBP. This BHQ domain of CBP has not been attributed to promote survival in any other neurodegenerative disorders.We have identified CBP as a genetic modifier of A?42 mediated neurodegeneration. Furthermore, we have identified BHQ domain of CBP is responsible for its neuroprotective function. These studies may have significant bearing on our understanding of genetic basis of AD.

Dataset Information

Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation.

Publications

Graded enhancement of p53 binding to CREB-binding protein (CBP) by multisite phosphorylation.

Similar Datasets

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