TAILIEUCHUNG - Báo cáo khoa học: Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm

Salt-inducible kinase-1 (SIK1) is phosphorylated at Ser577 by protein kinase A in adrenocorticotropic hormone-sti-mulated Y1 cells, and the phospho-SIK1 translocates from the nucleus to the cytoplasm. The phospho-SIK1 is dephosphorylated in the cytoplasmand re-enters thenucleus several hours later. By using green-fluorescent protein-tag-ged SIK1 fragments, we found that a peptide region (586– 612) was responsible for the nuclear localization of SIK1. Theregionwas namedthe RK-rich region because of its Arg- and Lys-rich nature. . | Eur. J. Biochem. 271 4307-4319 2004 FEBS 2004 doi Salt-inducible kinase-1 represses cAMP response element-binding protein activity both in the nucleus and in the cytoplasm Yoshiko Katoh1 . Hiroshi Takemori1 Li Min1 Masaaki Muraoka1 3. Junko Doi4. Nanao Horike1 and Mitsuhiro Okamoto1 2 1 Department of Biochemistry and Molecular Biology Graduate School of Medicine H-1 and 2Laboratories for Biomolecular Networks Graduate School of Frontier Biosciences Osaka University Japan 3ProteinExpress Co. Ltd Choshi Chiba Japan 4Department of Food and Nutrition Senri Kinran University Osaka Japan Salt-inducible kinase-1 SIK1 is phosphorylated at Ser577 by protein kinase A in adrenocorticotropic hormone-sti-mulated Y1 cells and the phospho-SIK1 translocates from the nucleus to the cytoplasm. The phospho-SIK1 is dephosphorylated in the cytoplasm and re-enters the nucleus several hours later. By using green-fluorescent protein-tagged SIK1 fragments we found that a peptide region 586612 was responsible for the nuclear localization of SIK1. The region was named the RK-rich region because of its Arg- and Lys-rich nature. SIK1s mutated in the RK-rich region were localized mainly in the cytoplasm. Because SIK1 represses cAMP-response element CRE -mediated transcription of steroidogenic genes the mutants were examined for their effect on transcription. To our surprise the cytoplasmic mutants strongly repressed the CRE-binding protein CREB activity the extent of repression being similar to that of SIK1 S577A a mutant localized exclusively in the nucleus. Several chimeras were constructed from SIK1 and from its isoform SIK2 which was localized mainly in the cytoplasm and they were examined for intracellular localization as well as CREB-repression activity. A SIK1-derived chimera where the RK-rich region had been replaced with the corresponding region of SIK2 was found in the cytoplasm its CREB-modulating activity being similar to that of wild-type SIK1. On .

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