Utilizing proteomic approach to identify nuclear translocation related serine kinase phosphorylation site of GNMT as downstream effector for benzo[a]pyrene |
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Authors: | Ming-Hui Yang Chen-Chung Liao Jung-Hsien Hung Xiu-Ting Lai Chia-Hung Yen Yi-Ming Arthur Chen |
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Affiliation: | 1. Institute of Biological Chemistry, Academia Sinica, Taipei, 11529, Taiwan;2. Center for Infectious Disease and Cancer Research (CICAR), Kaohsiung Medical University, Kaohsiung 80708, Taiwan;3. Master Program in Clinical Pharmacogenomics and Pharmacoproteomics, College of Pharmacy, Taipei Medical University, Taipei, 11031, Taiwan;4. Research Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan;5. Proteomics Research Center, National Yang-Ming University, Taipei 11221, Taiwan;6. Institute of Microbiology and Immunology, National Yang-Ming University, Taipei 11221, Taiwan;7. Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;8. Research Center for Natural products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan;9. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan |
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Abstract: | Glycine N-methyltransferase (GNMT) protein is highly expressed in certain tissues, such as liver, pancreas, and prostate. GNMT serves multiple roles which include a methyl group transfer enzyme and a liver tumor suppressor. Benzo(a)pyrene (BaP), a family member of polycyclic aromatic hydrocarbon (PAH), is a known environmental carcinogen found in coal tar, tobacco smoke, barbecued food and incomplete combustion of auto fuel. BaP recruits cytochrome P450 to transform itself into benzo(a)pyrene-7,8-diol-9,10-epoxide (B(a)PDE), which covalently interacts with DNA causing tumorigenesis. BaP can be detoxified through GNMT and induces GNMT translocation into the cellular nucleus. GNMT translocation is accompanied by phosphorylation, but the role of phosphorylation in GNMT remains to be explored. Using liquid chromatography coupled with tandem mass spectrometry, this study identified serine 9 of GNMT as the phosphorylation site upon BaP treatment. When serine 9 was mutated and lost the capability to be phosphorylated, the occurrence of BaP-induced GNMT nuclear translocation was dramatically decreased. Also, this mutant from of GNMT lost the ability of phosphorylation and increased cytochrome P450 1A1 (Cyp1a) expression upon BaP treatment. In addition, protein kinase C (PKC) and c-Jun NH2-terminal kinase (JNK) may be required for such phosphorylation. Further characterization of phosphorylated GNMT for its link to BaP may bring new insights into chemical detoxification. |
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Keywords: | Benzo(a)pyrene GNMT Phosphorylation |
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