Transcriptional regulation of tumor suppressor p53 by cAMP-responsive element-binding protein/AMP-activated protein kinase complex in response to glucose deprivation.
Tumor suppressor p53 plays a pivotal role in the regulation of cell fate determination in response to a variety of cellular stress including carbon source depletion. In this study, we found that cAMP-responsive element-binding protein (CREB) collaborates with AMP-activated protein kinase alpha (AMPKalpha) to regulate the transcription of p53. Luciferase reporter assays showed that the genomic fragment spanning from -531 to -239 of human p53 gene is required for the transactivation of p53 in response to glucose deprivation. Within this region, we found out a putative CREB-binding site. siRNA-mediated knockdown of CREB resulted in a significant inhibition of the up-regulation of p53 and apoptosis under glucose deprivation. Consistent with these observations, glucose deprivation induced the transcription of p53 and CREB. Additionally, glucose deprivation led to an efficient recruitment of CREB onto the promoter region of p53 gene carrying the canonical CREB-binding site, indicating that CREB has an ability to bind to the promoter region of p53 gene and transactivate p53. Furthermore, the amounts of CREB/phospo-AMPKalpha complex increased in response to glucose deprivation. Taken together, our present findings suggest that p53 is transcriptionally regulated by CREB/phospho-AMPKalpha complex and thereby contributing to the induction of apoptosis under carbon source depletion.
Okoshi
Rintaro
R
Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Ando
Kiyohiro
K
Suenaga
Yusuke
Y
Sang
Meixiang
M
Kubo
Natsumi
N
Kizaki
Harutoshi
H
Nakagawara
Akira
A
Ozaki
Toshinori
T
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D015151:Immunoblotting; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008156:Luciferases / Q000378:metabolism; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism*
C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D012333:RNA, Messenger; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008156:Luciferases; D055372:AMP-Activated Protein Kinases; D005947:Glucose