Cooperative roles of c-Abl and Cdk5 in regulation of p53 in response to oxidative stress.
The p53 tumor suppressor protein, a critical modulator of cellular stress responses, is activated through diverse mechanisms that result in its stabilization and transcriptional activation. p53 activity is controlled by transcriptional, translational, and post-translational regulation. The major mechanisms of p53 regulation occur primarily through interactions with HDM2, an E3 ubiquitin ligase that leads to p53 nuclear export and degradation. Here, we demonstrate that hydrogen peroxide-induced oxidative stress elicits down-regulation of HDM2. c-Abl mediates down-regulation of HDM2, leading to an increase of p53 level. Moreover, Cdk5 (cyclin-dependent kinase 5), a proline-directed Ser/Thr kinase, additionally increases p53 stability via post-translational modification of p53 in response to hydrogen peroxide. The p53 protein stabilized by c-Abl and Cdk5 is transcriptionally active; however, transcription of its target gene is differentially regulated with selective binding of p53 on promoter regions of its target genes by c-Abl. In addition, c-Abl modulates Cdk5 activity via phosphorylation of tyrosine 15 in cooperation with cleavage of p35 to p25. Our results show that c-Abl and Cdk5 cooperatively regulate maximal activation of p53, resulting in neuronal death in response to oxidative stress by hydrogen peroxide. These findings aid in clarifying the mechanism underlying the occurrence of neuronal apoptosis as a result of c-Abl and Cdk5-mediated p53 stabilization and transcriptional activation.
Lee
Jong-Hee
JH
Department of Life Science, Division of Molecular and Life Science, Systems-Biodynamics National Care Research Center, Pohang University of Science and Technology, Pohang 790-784, Republic of Korea.
Jeong
Min-Woo
MW
Kim
Wanil
W
Choi
Yoon Ha
YH
Kim
Kyong-Tai
KT
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D048868:Adaptor Proteins, Signal Transducing; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C500695:CDCA5 protein, human; D018797:Cell Cycle Proteins; D016877:Oxidants; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D044767:Ubiquitin-Protein Ligases; D016315:Proto-Oncogene Proteins c-abl; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human