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Int J Biochem Cell Biol. 2016 Nov;80:132-142. doi: 10.1016/j.biocel.2016.09.029. Epub 2016 Oct 1.

Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence.

Author information

1
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 20031, China.
2
The Fourth Hospital of Hebei Medical University, 12 Jiankang Rd, Qiao Dong Qu, Shijiazhuang, Hebei, 050012, China.
3
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 20031, China; Department of Biochemistry and Molecular Biology, Institute of Basic Medicine, Hebei Medical University, 361 Zhongshan E Rd, Chang'an, Shijiazhuang, Hebei, 050017, China.
4
Hospital of Lanzhou Military Command, 333 South Binhe Road, Lanzhou 730050, China.
5
Tianjin Haihe Hospital, Tianjin Institute of Respiratory Diseases, Jingu Road, Jinnan District, Tianjin, 300350, China.
6
Department of Physiology, The University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 634a, Oklahoma City, OK 73104, USA; School of Biological Sciences, The University of Hong Kong, 5N09, Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong.
7
Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 20031, China. Electronic address: zxliu@sibs.ac.cn.

Abstract

Microphthalmia-associated transcription factor (MITF) plays a crucial role in the melanogenesis and proliferation of melanocytes that is dependent on its abundance and modification. Here, we report that epidermal growth factor (EGF) induces senescence and cyclin-dependent kinase inhibitor 1A (CDKN1A) expression that is related to MITF. We found that MITF could bind TP53 to regulate CDKN1A. Furthermore, the interaction between MITF and TP53 is dependent on AKT activity. We found that AKT phosphorylates MITF at S510. Phosphorylated MITF S510 enhances its affinity to TP53 and promotes CDKN1A expression. Meanwhile, the unphosphorylative MITF promotes TYR expression. The levels of p-MITF-S510 are low in 90% human melanoma samples. Thus the level of p-MITF-S510 could be a possible diagnostic marker for melanoma. Our findings reveal a mechanism for regulating MITF functions in response to EGF stimulation and suggest a possible implementation for preventing the over proliferation of melanoma cells.

KEYWORDS:

AKT; MITF; Phosphorylation; Senescence; TP53

PMID:
27702651
DOI:
10.1016/j.biocel.2016.09.029
[Indexed for MEDLINE]
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