G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis.
G-protein-coupled receptor kinases (GRKs) are an important family of Ser/Thr kinases that specifically phosphorylate and desensitize the activated receptor in response to environmental stimulation. Here we identify p53, a key tumor suppressor, as a novel GRK substrate in vivo, revealing a previously unknown function of GRKs in regulation of genome stability. Knockdown GRK5 in osteosarcoma cells inhibits DNA damage-induced apoptosis via a p53-mediated mechanism. Furthermore, GRK5, but not GRK2 or GRK6, phosphorylates p53 at Thr-55, which promotes the degradation of p53, leading to inhibition of p53-dependent apoptotic response to genotoxic damage. Consistently, the increase of p53 and irradiation-induced apoptosis were observed in GRK5-deficient mice. These results demonstrate GRK5 as a novel kinase of p53, as well as a negative regulator of p53-mediated signal transduction.
Chen
Xiaoqing
X
State Key Laboratory of Medical Neurobiology and Pharmacology Research Center, Shanghai Medical College and Institutes of Brain Science, Fudan University, Shanghai 200032, China.
Zhu
Huiling
H
Yuan
Man
M
Fu
Jie
J
Zhou
Yuqing
Y
Ma
Lan
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics / Q000502:physiology* / Q000528:radiation effects; D054774:G-Protein-Coupled Receptor Kinase 5 / Q000235:genetics / Q000378:metabolism*; D005720:Gamma Rays / Q000009:adverse effects; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D054774:G-Protein-Coupled Receptor Kinase 5; C517898:GRK5 protein, human; C517895:Grk5 protein, mouse