title: Phorbol 12-myristate 13-acetate promotes nuclear translocation of hepatic steroid response element binding protein-2.
abstract: Sterol regulatory element-binding protein (SREBP)-2 is a pivotal transcriptional factor in cholesterol metabolism. Factors interfering with the proper functioning of SREBP-2 potentially alter plasma lipid profiles. Phorbol 12-myristate 13-acetate (PMA), which is a common protein kinase C (PKC) activator, was shown to promote the post-translational processing and nuclear translocation of SREBP-2 in hepatic cells in the current study. Following SREBP-2 translocation, the transcripts of its target genes HMGCR and LDLR were upregulated as demonstrated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Electrophoretic mobility shift assays (EMSA) also demonstrated an induced DNA-binding activity on the sterol response element (SRE) domain under PMA treatment. The increase of activated Srebp-2 without the concurrent induced mRNA expression was also observed in an animal model. As the expression of SREBP-2 was not increased by PMA, the activation of PKC was the focus of investigation. Specific PKC isozyme inhibition and overexpression supported that PKCβ was responsible for the promoting effect. Further studies showed that the mitogen-activated protein kinases (MAPKs) extracellular signal-regulated kinases (ERK) and c-Jun N-terminal kinases (JNK), but not 5' adenosine monophosphate-activated protein kinase (AMPK), were the possible downstream signaling proteins of PKCβ. In conclusion, this study illustrated that PKCβ increased SREBP-2 nuclear translocation in a pathway mediated by MEK/ERK and JNK, rather than the one dictated by AMPK. These results revealed a novel signaling target of PKCβ in the liver cells.
authors.affiliation: Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Tsz Yan
authors.initials: TY
authors.lastname: Wong
authors.affiliation: Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong.
authors.forename: Yan Qin
authors.initials: YQ
authors.lastname: Tan
authors.affiliation: Dept. of Food Science, National Chiayi University, Chiayi City, Taiwan, ROC.
authors.forename: Shu-Mei
authors.initials: SM
authors.lastname: Lin
authors.affiliation: Food and Nutritional Sciences Programme, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong; Biochemistry Programmes, School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Shatin, Hong Kong. Electronic address: laikleung@cuhk.edu.hk.
authors.forename: Lai K
authors.initials: LK
authors.lastname: Leung
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics; D011494:Protein Kinases / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics; D051782:Sterol Regulatory Element Binding Protein 2 / Q000737:chemistry / Q000378:metabolism*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*
chemical_list: C573412:LDLR protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; D051782:Sterol Regulatory Element Binding Protein 2; C553220:HMGCR protein, human; D006903:Hydroxymethylglutaryl CoA Reductases; D011494:Protein Kinases; D013755:Tetradecanoylphorbol Acetate
keywords: Liver; PKC; Phorbol ester; SREBP-2