ARF-dependent regulation of ATM and p53 associated KZNF (Apak) protein activity in response to oncogenic stress.
The KRAB-type zinc-finger protein Apak (ATM and p53 associated KZNF protein) specifically suppresses p53-mediated apoptosis. Upon DNA damage, Apak is phosphorylated and inhibited by ATM kinase, resulting in p53 activation. However, how Apak is regulated in response to oncogenic stress remains unknown. Here we show that upon oncogene activation, Apak is inhibited in the tumor suppressor ARF-dependent but ATM-independent manner. Oncogene-induced ARF protein directly interacts with Apak and competes with p53 to bind to Apak, resulting in Apak dissociation from p53. Thus, Apak is differentially regulated in the ARF and ATM-dependent manner in response to oncogenic stress and DNA damage, respectively.
Wang
Shan
S
State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, China.
Tian
Chunyan
C
Xing
Guichun
G
Gao
Mei
M
Jiao
Wenjuan
W
Xiao
Tingting
T
Yin
Yuxin
Y
He
Fuchu
F
Zhang
Lingqiang
L
D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis*; D064007:Ataxia Telangiectasia Mutated Proteins; D002352:Carrier Proteins / Q000096:biosynthesis*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D034622:RNA Interference; D013312:Stress, Physiological; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D016335:Zinc Fingers
D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; 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