Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.

Piyajit Watcharasit, Gautam N. Bijur, Ling Song, Jianhui Zhu, Xinbin Chen, Richard S. Jope

Research output: Contribution to journalArticle

210 Citations (Scopus)

Abstract

The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3beta (GSK3beta), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3beta. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3beta binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3beta. Deletion of the p53 basic domain (BD) abrogated GSK3beta binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3beta. GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53. This regulatory role of GSK3beta was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3beta was inhibited. Besides promoting p53-mediated transcription, GSK3beta also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3beta co-immunoprecipitated with p53 and was activated, and inhibition of GSK3beta blocked cytochrome c release and caspase-3 activation. Thus, GSK3beta interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.

Original languageEnglish (US)
Pages (from-to)48872-48879
Number of pages8
JournalThe Journal of biological chemistry
Volume278
Issue number49
StatePublished - Dec 5 2003
Externally publishedYes

Fingerprint

Glycogen Synthase Kinases
Chemical activation
Mitochondria
Transcription
Cytochromes c

ASJC Scopus subject areas

  • Biochemistry

Cite this

Watcharasit, P., Bijur, G. N., Song, L., Zhu, J., Chen, X., & Jope, R. S. (2003). Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. The Journal of biological chemistry, 278(49), 48872-48879.

Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. / Watcharasit, Piyajit; Bijur, Gautam N.; Song, Ling; Zhu, Jianhui; Chen, Xinbin; Jope, Richard S.

In: The Journal of biological chemistry, Vol. 278, No. 49, 05.12.2003, p. 48872-48879.

Research output: Contribution to journalArticle

Watcharasit, P, Bijur, GN, Song, L, Zhu, J, Chen, X & Jope, RS 2003, 'Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.', The Journal of biological chemistry, vol. 278, no. 49, pp. 48872-48879.
Watcharasit, Piyajit ; Bijur, Gautam N. ; Song, Ling ; Zhu, Jianhui ; Chen, Xinbin ; Jope, Richard S. / Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53. In: The Journal of biological chemistry. 2003 ; Vol. 278, No. 49. pp. 48872-48879.
@article{60383f88e3ea48719047d5a676d046ae,
title = "Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.",
abstract = "The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3beta (GSK3beta), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3beta. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3beta binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3beta. Deletion of the p53 basic domain (BD) abrogated GSK3beta binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3beta. GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53. This regulatory role of GSK3beta was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3beta was inhibited. Besides promoting p53-mediated transcription, GSK3beta also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3beta co-immunoprecipitated with p53 and was activated, and inhibition of GSK3beta blocked cytochrome c release and caspase-3 activation. Thus, GSK3beta interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.",
author = "Piyajit Watcharasit and Bijur, {Gautam N.} and Ling Song and Jianhui Zhu and Xinbin Chen and Jope, {Richard S.}",
year = "2003",
month = "12",
day = "5",
language = "English (US)",
volume = "278",
pages = "48872--48879",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "49",

}

TY - JOUR

T1 - Glycogen synthase kinase-3beta (GSK3beta) binds to and promotes the actions of p53.

AU - Watcharasit, Piyajit

AU - Bijur, Gautam N.

AU - Song, Ling

AU - Zhu, Jianhui

AU - Chen, Xinbin

AU - Jope, Richard S.

PY - 2003/12/5

Y1 - 2003/12/5

N2 - The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3beta (GSK3beta), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3beta. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3beta binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3beta. Deletion of the p53 basic domain (BD) abrogated GSK3beta binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3beta. GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53. This regulatory role of GSK3beta was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3beta was inhibited. Besides promoting p53-mediated transcription, GSK3beta also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3beta co-immunoprecipitated with p53 and was activated, and inhibition of GSK3beta blocked cytochrome c release and caspase-3 activation. Thus, GSK3beta interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.

AB - The recent discovery of direct interactions between two important regulators of cell fate, the tumor suppressor p53 and glycogen synthase kinase-3beta (GSK3beta), led us to examine the mechanism and outcomes of this interaction. Two regions of p53 were identified that regulate its binding to GSK3beta. Deletion of the p53 activation domain-1 (AD1), but not mutations that prevent MDM2 binding through the AD1 domain, enhanced GSK3beta binding to p53, indicating that the AD1 domain interferes with p53 binding to GSK3beta. Deletion of the p53 basic domain (BD) abrogated GSK3beta binding, and a ten amino acid region within the C-terminal BD domain was identified as necessary for binding to GSK3beta. GSK3beta activity was not required for p53 binding, but inhibition of GSK3beta stabilized the association, suggesting a transient interaction during which active GSK3beta promotes actions of p53. This regulatory role of GSK3beta was demonstrated by large reductions of p53-induced increases in the levels of MDM2, p21, and Bax when GSK3beta was inhibited. Besides promoting p53-mediated transcription, GSK3beta also contributed to mitochondrial p53 apoptotic signaling. After DNA damage, mitochondrial GSK3beta co-immunoprecipitated with p53 and was activated, and inhibition of GSK3beta blocked cytochrome c release and caspase-3 activation. Thus, GSK3beta interacts with p53 in both the nucleus and mitochondria and promotes its actions at both sites.

UR - http://www.scopus.com/inward/record.url?scp=0442274617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0442274617&partnerID=8YFLogxK

M3 - Article

C2 - 14523002

AN - SCOPUS:0442274617

VL - 278

SP - 48872

EP - 48879

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 49

ER -