Gadd45a contributes to p53 stabilization in response to DNA damage.
p53 is an important molecule in cellular response to DNA damage. After genotoxic stress, p53 protein stabilizes transiently and accumulates in the nucleus, where it functions as a transcription factor and upregulates multiple downstream-targeted genes, including p21(Waf1/Cip1), Gadd45a and Bax. However, regulation of p53 stabilization is complex and may mainly involve post-translational modification of p53, such as phosphorylation and acetylation. Using mouse embryonic fibroblasts (MEFs) derived from Gadd45a knockouts, we found that disruption of Gadd45a greatly abolished p53 protein stabilization following UVB treatment. Phosphorylation of p53 at Ser-15 was substantially reduced in Gadd45a-/- MEFs. In addition, p53 induction by UVB was shown to be greatly abrogated in the presence of p38 kinase inhibitor, but not c-Jun N-terminal kinase (JNK) and extracellular-signal regulated kinase (ERK), suggesting that p38 protein kinase is involved in the regulation of p53 induction. Along with the findings presented above, inducible expression of Gadd45a enhanced p53 accumulation after cell exposure to UVB. Taken together, the current study demonstrates that Gadd45a, a conventional downstream gene of p53, may play a role as an upstream effector in p53 stabilization following DNA damage, and thus has defined a positive feedback signal in the activation of the p53 pathway.
Jin
Shunqian
S
State Key Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing 100021, China.
Mazzacurati
Lucia
L
Zhu
Xiaocheng
X
Tong
Tong
T
Song
Yongmei
Y
Shujuan
Shao
S
Petrik
Kimberly L
KL
Rajasekaran
Baskaran
B
Wu
Min
M
Zhan
Qimin
Q
D000818:Animals; D018797:Cell Cycle Proteins; D004249:DNA Damage / Q000528:radiation effects; D005347:Fibroblasts / Q000378:metabolism / Q000528:radiation effects; D051379:Mice; D009687:Nuclear Proteins / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53; C499072:Gadd45a protein, mouse; D000097642:GADD45 Proteins