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Mitogen- and stress-activated protein kinase 1 is required for gonadotropin-releasing hormone-mediated activation of gonadotropin α-subunit expression.
- Source :
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The Journal of biological chemistry [J Biol Chem] 2017 Dec 15; Vol. 292 (50), pp. 20720-20731. Date of Electronic Publication: 2017 Oct 20. - Publication Year :
- 2017
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Abstract
- Pituitary gonadotropin hormones are regulated by gonadotropin-releasing hormone (GnRH) via MAPK signaling pathways that stimulate gene transcription of the common α-subunit ( Cga ) and the hormone-specific β-subunits of gonadotropin. We have reported previously that GnRH-induced activities at these genes include various histone modifications, but we did not examine histone phosphorylation. This modification adds a negative charge to residues of the histone tails that interact with the negatively charged DNA, is associated with closed chromatin during mitosis, but is increased at certain genes for transcriptional activation. Thus, the functions of this modification are unclear. We initially hypothesized that GnRH might induce phosphorylation of Ser-10 in histone 3 (H3S10p) as part of its regulation of gonadotropin gene expression, possibly involving cross-talk with H3K9 acetylation. We found that GnRH increases the levels of both modifications around the Cga gene transcriptional start site and that JNK inhibition dramatically reduces H3S10p levels. However, this modification had only a minor effect on Cga expression and no effect on H3K9ac. GnRH also increased H3S28p and H3K27ac levels and also those of activated mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 inhibition dramatically reduced H3S28p levels in untreated and GnRH-treated cells and also affected H3K27ac levels. Although not affecting basal Cga expression, MSK1/2 inhibition repressed GnRH activation of Cga expression. Moreover, ChIP analysis revealed that GnRH-activated MSK1 targets the first nucleosome just downstream from the TSS. Given that the elongating RNA polymerase II (RNAPII) stalls at this well positioned nucleosome, GnRH-induced H3S28p, possibly in association with H3K27ac, would facilitate the progression of RNAPII.<br /> (© 2017 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Acetylation drug effects
Animals
Cell Line
Chromatin Immunoprecipitation
Glycoprotein Hormones, alpha Subunit genetics
Glycoprotein Hormones, alpha Subunit metabolism
Gonadotrophs drug effects
Gonadotrophs enzymology
Histones metabolism
Lysine metabolism
MAP Kinase Signaling System drug effects
Mice
Nucleosomes enzymology
Phosphorylation drug effects
Protein Kinase Inhibitors pharmacology
Protein Processing, Post-Translational drug effects
Receptors, LHRH agonists
Receptors, LHRH metabolism
Ribosomal Protein S6 Kinases, 90-kDa antagonists & inhibitors
Ribosomal Protein S6 Kinases, 90-kDa genetics
Serine metabolism
Gene Expression Regulation drug effects
Glycoprotein Hormones, alpha Subunit agonists
Gonadotrophs metabolism
Gonadotropin-Releasing Hormone metabolism
Nucleosomes metabolism
Ribosomal Protein S6 Kinases, 90-kDa metabolism
Transcription Initiation Site drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 292
- Issue :
- 50
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 29054929
- Full Text :
- https://doi.org/10.1074/jbc.M117.797845