UV-radiation induces dose-dependent regulation of p53 response and modulates p53-HDM2 interaction in human fibroblasts

• Published in: Oncogene Vol. 20; no. 46; pp. 6784 - 6793
• Main Authors: LATONEN, Leena, TAYA, Yoichi, LAIHO, Marikki
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 11.10.2001; Nature Publishing Group
• Subjects: Apoptosis; Bcl-2 protein; bcl-2-Associated X Protein; Biological and medical sciences; Blotting, Northern; Bromodeoxyuridine - metabolism; Cell cycle; Cell Line; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cyclin-Dependent Kinase Inhibitor p21; Cyclins - metabolism; Diploids; DNA damage; Dose-Response Relationship, Radiation; Fibroblasts; Fibroblasts - metabolism; Flow Cytometry; Fundamental and applied biological sciences. Psychology; GADD45 protein; GADD45 Proteins; Gene Expression Regulation; Gene regulation; Genes; HDM2 gene; Humans; Immunoblotting; Intracellular Signaling Peptides and Proteins; Kinases; Molecular and cellular biology; Nuclear Proteins; Oxidative stress; p53 Protein; Phosphorylation; Precipitin Tests; Protein Binding; Proteins; Proteins - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogene Proteins c-mdm2; Radiation; Serine - chemistry; Time Factors; Tumor suppressor genes; Tumor Suppressor Protein p53 - biosynthesis; Tumor Suppressor Protein p53 - metabolism; Tumors; Ultraviolet radiation; Ultraviolet Rays; Human; Regulation(control); TP53 Gene; Interaction; Modulation; Radiation; Regulation; Fibroblast
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1204883

We address here the effects of increasing fluencies of UV-radiation on stability, modifications, activity and HDM2-interactions of endogenous p53 tumor suppressor and on cellular damage response of human diploid fibroblasts. Low amounts of UVB/C-radiation induced a transient cell cycle arrest of the cells which correlated with rapid but transient increase in p53 levels. In contrast, high UV-fluency caused cell apoptosis and a slower but sustained increase in p53. Regulation of p53 target genes was highly dependent on the radiation dose used. Whereas low doses induced p21/Cip1/Waf1 and HDM2, high doses induced only GADD45 and BAX increasing the BAX:BCL-2 ratio. The levels of HDM2, a negative regulator of p53, increased only by the low dose of UVC and p53-HDM2 association was promoted. In the absence of HDM2-induction after the high dose of UV-radiation p53-HDM2-interaction was promoted, but HDM2 failed to downregulate p53. p53 site-specific modifications (Ser15, Ser33, Ser37, Lys382) varied kinetically and were dependent on the fluency of the radiation used. Maximal phosphorylation of p53 on Ser15 and Ser33 correlated with increased levels of HDM2-free p53. The results suggest that regulation of p53 and HDM2 by UV-radiation is highly dose-dependent and contributes to the outcome of the cellular response.