MiTF links Erk1/2 kinase and p21CIP1/WAF1 activation after UVC radiation in normal human melanocytes and melanoma cells

Molecular Cancer

Research

Angela Garcia¹  Yu Kong²  Amarinder Singh³  Feng Liu⁴  Frank L Meyskens⁵  Zhen Yang⁶ 

[1] Chao Family Comprehensive Cancer Center, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Chao Family Comprehensive Cancer Center, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Department of Chemistry, School of Life Science, Xi'an Jiao Tong University, 710049, Xi'an, Shaanxi Province, China;Department of Biological Sciences, University of California-Irvine, 92617, Irvine, CA, USA;Department of Medicine, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Chao Family Comprehensive Cancer Center, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Department of Medicine, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Chao Family Comprehensive Cancer Center, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Department of Biological Sciences, University of California-Irvine, 92617, Irvine, CA, USA;Department of Medicine, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Chao Family Comprehensive Cancer Center, University of California-Irvine School of Medicine, 92868, Orange, CA, USA;Shandong Provincial Hospital, Jingwu Road, 250021, Shandong Province, China;

关键词: Melanoma Cell;    Melanoma Cell Line;    Ataxia Telangiectasia Mutate;    Enhance Cell Survival;    MiTF Expression;   

DOI  :  10.1186/1476-4598-9-214

 received in 2010-01-19, accepted in 2010-08-11,  发布年份 2010

来源: Springer

【 摘 要 】

As a survival factor for melanocytes lineage cells, MiTF plays multiple roles in development and melanomagenesis. What role MiTF plays in the DNA damage response is currently unknown. In this report we observed that MiTF was phosphorylated at serine 73 after UVC radiation, which was followed by proteasome-mediated degradation. Unlike after c-Kit stimulation, inhibiting p90RSK-1 did not abolish the band shift of MiTF protein, nor did it abolish the UVC-mediated MiTF degradation, suggesting that phosphorylation on serine 73 by Erk1/2 is a key event after UVC. Furthermore, the MiTF-S73A mutant (Serine 73 changed to Alanine via site-directed mutagenesis) was unable to degrade and was continuously expressed after UVC exposure. Compared to A375 melanoma cells expressing wild-type MiTF (MiTF-WT), cells expressing MiTF-S73A mutant showed less p21WAF1/CIP1 accumulation and a delayed p21WAF1/CIP1 recovery after UVC. Consequently, cells expressing MiTF-WT showed a temporary G1 arrest after UVC, but cells expressing MiTF-S73A mutant or lack of MiTF expression did not. Finally, cell lines with high levels of MiTF expression showed higher resistance to UVC-induced cell death than those with low-level MiTF. These data suggest that MiTF mediates a survival signal linking Erk1/2 activation and p21WAF1/CIP1 regulation via phosphorylation on serine 73, which facilitates cell cycle arrest. In addition, our data also showed that exposure to different wavelengths of UV light elicited different signal pathways involving MiTF.

【 授权许可】

CC BY   
© Liu et al; licensee BioMed Central Ltd. 2010