SIK (Salt-inducible kinase): regulation of ACTH-mediated steroidogenic gene expression and nuclear/cytosol redistribution.
Possible involvement of salt-inducible kinase (SIK), a serine/threonine protein kinase first cloned from high K+-diet treated rat adrenal glands, in the regulation of steroidogenesis was investigated. Y-1 cells, when treated with ACTH, underwent a rapid change in SIK's mRNA content. It reached the maximum within a few hours and returned to the base after 8 h. In contrast, the levels of mRNAs for CYP11A and StAR protein reached the maxima after 8 h. The SIK's mRNA induction failed to occur in ACTH-, forskolin- or 8-Br-cAMP-treated Kin-7 cells, a mutant cell line of Y-1 with defective cAMP-dependent protein kinase A (PKA). Y-1 cells that overexpress SIK, when treated with ACTH, had significantly repressed levels of mRNAs for CYP11A and StAR protein. Therefore, SIK might have a negative effect on the CYP11A- and StAR protein-gene expression in the early phase of ACTH-mediated steroidogenesis. To further explore the mechanisms underlying this phenomenon, we examined intracellular distribution of the green fluorescence protein (GFP)-tagged SIK. When GFP-SIK was introduced into HeLa cells, the fluorescent signals were detected in the nucleus. In Y-1 cells GFP-SIK was detected both in the nucleus and cytosol, and the signal in the former moved to the latter after ACTH-treatment. The nuclear/cytosol re-distribution of GFP-SIK was also observed in forskolin- or 8-Br-cAMP-treated Y-1 cells, but not in Kin-7 cells. These results suggest that the intracellular re-distribution of SIK in Y-1 cells may depend on the cAMP/PKA signaling pathway and has an important regulatory role in the ACTH-mediated steroidogenic gene expression.
Lin
X
X
Department of Molecular Physiological Chemistry, Osaka University Medical School, Japan.
Takemori
H
H
Doi
J
J
Katoh
Y
Y
Okamoto
M
M
D000302:Adrenal Cortex / Q000166:cytology / Q000378:metabolism; D000305:Adrenal Cortex Hormones / Q000235:genetics* / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000502:physiology*; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics; D000242:Cyclic AMP / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D003600:Cytosol / Q000378:metabolism*; D015536:Down-Regulation; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D011401:Promoter Regions, Genetic / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D014018:Tissue Distribution
D000305:Adrenal Cortex Hormones; D012333:RNA, Messenger; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D002786:Cholesterol Side-Chain Cleavage Enzyme; D017346:Protein Serine-Threonine Kinases; C120299:Sik1 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases