Differential regulation of Apak by various DNA damage signals.
The tumor suppressor p53 lies at the center of a protein-signaling network that responds to many types of stress, and p53 activation leads to cell cycle arrest or apoptosis. We recently identified ATM and p53-associated KZNF protein (Apak) as a negative regulator of p53-mediated apoptosis. After treatment of cells with methyl methanesulfonate (MMS), Apak is phosphorylated by ATM kinase and dissociates from p53, resulting in p53 activation and induction of apoptosis. However, the mechanism by which Apak is regulated in response to other types of DNA damage signals remains unclear. Here, we show that four of seven types of DNA damage signals we examined (induction by etoposide, doxorubicin, camptothecin and cisplatin treatment) resulted in significant Apak phosphorylation and dissociation of Apak from p53, releasing the inhibition of p53 transcriptional activity. In contrast, Apak was not phosphorylated at Ser68 after 5-fluorouracil or alpha-lipoic acid treatment and persistently inhibited p53 activity. These findings provide evidence that the Apak-p53 interaction is regulated differentially by various DNA damage signals.
Wang
Shan
S
College of Animal Science and Technology, Shaanxi Key Laboratory of Molecular Biology for Agriculture, Northwest A&F University, 712100, Yangling, Shaanxi, China.
Tian
Chunyan
C
Xiao
Tingting
T
Xiao
Tingtiang
T
Xing
Guichun
G
He
Fuchu
F
Zhang
Lingqiang
L
Chen
Hong
H
D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000235:genetics*; D018797:Cell Cycle Proteins; D002460:Cell Line; D004249:DNA Damage / Q000187:drug effects; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases; D015398:Signal Transduction / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000235:genetics; D025521:Tumor Suppressor Proteins
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C540923:ZNF420 protein, human; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases