title: CREB represses p53-dependent transactivation of MDM2 through the complex formation with p53 and contributes to p53-mediated apoptosis in response to glucose deprivation.
abstract: Recently, we have described that CREB (cAMP-responsive element-binding protein) has the ability to transactivate tumor suppressor p53 gene in response to glucose deprivation. In this study, we have found that CREB forms a complex with p53 and represses p53-mediated transactivation of MDM2 but not of p21(WAF1). Immunoprecipitation analysis revealed that CREB interacts with p53 in response to glucose deprivation. Forced expression of CREB significantly attenuated the up-regulation of the endogenous MDM2 in response to p53. By contrast, the mutant form of CREB lacking DNA-binding domain (CREBΔ) had an undetectable effect on the expression level of the endogenous MDM2. During the glucose deprivation-mediated apoptosis, there existed an inverse relationship between the expression levels of MDM2 and p53/CREB. Additionally, p53/CREB complex was dissociated from MDM2 promoter in response to glucose deprivation. Collectively, our present results suggest that CREB preferentially down-regulates MDM2 and thereby contributing to p53-mediated apoptosis in response to glucose deprivation.
authors.affiliation: Laboratory of Anti-tumor Research, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
authors.forename: Rintaro
authors.initials: R
authors.lastname: Okoshi
authors.forename: Natsumi
authors.initials: N
authors.lastname: Kubo
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nakashima
authors.forename: Osamu
authors.initials: O
authors.lastname: Shimozato
authors.forename: Akira
authors.initials: A
authors.lastname: Nakagawara
authors.forename: Toshinori
authors.initials: T
authors.lastname: Ozaki
mesh_terms: D017209:Apoptosis; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D015536:Down-Regulation; D005947:Glucose / Q000172:deficiency*; D006801:Humans; D017434:Protein Structure, Tertiary / Q000235:genetics; D051736:Proto-Oncogene Proteins c-mdm2 / Q000037:antagonists & inhibitors* / Q000235:genetics*; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D005947:Glucose