title: Phosphorylation of MITF by AKT affects its downstream targets and causes TP53-dependent cell senescence.
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.
authors.affiliation: 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.
authors.forename: Chenyao
authors.initials: C
authors.lastname: Wang
authors.affiliation: The Fourth Hospital of Hebei Medical University, 12 Jiankang Rd, Qiao Dong Qu, Shijiazhuang, Hebei, 050012, China.
authors.forename: Lu
authors.initials: L
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Qian
authors.initials: Q
authors.lastname: Su
authors.affiliation: Hospital of Lanzhou Military Command, 333 South Binhe Road, Lanzhou 730050, China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Fan
authors.affiliation: The Fourth Hospital of Hebei Medical University, 12 Jiankang Rd, Qiao Dong Qu, Shijiazhuang, Hebei, 050012, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Fourth Hospital of Hebei Medical University, 12 Jiankang Rd, Qiao Dong Qu, Shijiazhuang, Hebei, 050012, China.
authors.forename: Shunqiang
authors.initials: S
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Huafei
authors.initials: H
authors.lastname: Wang
authors.affiliation: Tianjin Haihe Hospital, Tianjin Institute of Respiratory Diseases, Jingu Road, Jinnan District, Tianjin, 300350, China.
authors.forename: Huaiyong
authors.initials: H
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Chi Bun
authors.initials: CB
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Zhixue
authors.initials: Z
authors.lastname: Liu
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051739:Microphthalmia-Associated Transcription Factor / Q000378:metabolism*; D010766:Phosphorylation; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D051739:Microphthalmia-Associated Transcription Factor; D016159:Tumor Suppressor Protein p53; D051057:Proto-Oncogene Proteins c-akt
keywords: AKT; MITF; Phosphorylation; Senescence; TP53