Gadd45a contributes to p53 stabilization in response to DNA damage

• Published in: Oncogene Vol. 22; no. 52; pp. 8536 - 8540
• Main Authors: SHUNQIAN JIN, MAZZACURATI, Lucia, XIAOCHENG ZHU, TONG TONG, YONGMEI SONG, SHAO SHUJUAN, PETRIK, Kimberly L, RAJASEKARAN, Baskaran, MIN WU, QIMIN ZHAN
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 20-11-2003; Nature Publishing Group
• Subjects: Acetylation; Animals; Bax protein; Biological and medical sciences; c-Jun protein; Cancer; Cell cycle; Cell Cycle Proteins; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-dependent kinase inhibitor p21; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - radiation effects; Embryo fibroblasts; Enzyme inhibitors; Extracellular signal-regulated kinase; Fibroblasts - metabolism; Fibroblasts - radiation effects; Fundamental and applied biological sciences. Psychology; Gadd45A protein; Genes; Genotoxicity; JNK protein; Kinases; Mice; Molecular and cellular biology; Nuclear Proteins - metabolism; Oncology; p38 Protein; p53 Protein; Phosphorylation; Post-translation; Protein kinase; Proteins; Transcription factors; Tumor Suppressor Protein p53 - metabolism; Tumorigenesis; Ultraviolet radiation; Ultraviolet Rays; United States > US; Pittsburgh Pennsylvania; TP53 Gene; DNA; DNA damage; Gadd45a; Lesion; Carcinogenesis; Tumor suppressor gene; p53
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206907

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.