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 language | English (US) |
|---|---|
| Pages (from-to) | 48872-48879 |
| Number of pages | 8 |
| Journal | The Journal of biological chemistry |
| Volume | 278 |
| Issue number | 49 |
| State | Published - Dec 5 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry
Cite this
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 journal › Article
}
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.
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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 -