Follicle-stimulating hormone stimulates protein kinase A-mediated histone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cells.
We examined the phosphorylation and acetylation of histone H3 in ovarian granulosa cells stimulated to differentiate by follicle-stimulating hormone (FSH). We found that protein kinase A (PKA) mediates H3 phosphorylation on serine 10, based on inhibition exclusively by PKA inhibitors. FSH-stimulated H3 phosphorylation in granulosa cells is not downstream of mitogen-activated protein kinase/extracellular signal-regulated kinase, ribosomal S6 kinase-2, mitogen- and stress-activated protein kinase-1, p38 MAPK, phosphatidylinositol-3 kinase, or protein kinase C. Transcriptional activation-associated H3 phosphorylation on serine 10 and acetylation of lysine 14 leads to activation of serum glucocorticoid kinase, inhibin alpha, and c-fos genes. We propose that phosphorylation of histone H3 on serine 10 by PKA in coordination with acetylation of H3 on lysine 14 results in reorganization of the promoters of select FSH responsive genes into a more accessible configuration for activation. The unique role of PKA as the physiological histone H3 kinase is consistent with the central role of PKA in initiating granulosa cell differentiation.
Salvador
L M
LM
Department of Cell and Molecular Biology, Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, IL 60611, USA.
Park
Y
Y
Cottom
J
J
Maizels
E T
ET
Jones
J C
JC
Schillace
R V
RV
Carr
D W
DW
Cheung
P
P
Allis
C D
CD
Jameson
J L
JL
Hunzicker-Dunn
M
M
D000107:Acetylation; D000818:Animals; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D017874:Immediate-Early Proteins; D007265:Inhibins / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D009687:Nuclear Proteins; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011980:Receptors, Progesterone / Q000235:genetics; D015398:Signal Transduction; D015533:Transcriptional Activation; D000099184:Serum-Glucocorticoid Regulated Kinases
D017868:Cyclic AMP-Dependent Protein Kinases; D004268:DNA-Binding Proteins; D005640:Follicle Stimulating Hormone; D006657:Histones; D017874:Immediate-Early Proteins; D007265:Inhibins; D020928:Mitogen-Activated Protein Kinases; D009687:Nuclear Proteins; D010750:Phosphoproteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D016760:Proto-Oncogene Proteins c-fos; D011980:Receptors, Progesterone; D000099184:Serum-Glucocorticoid Regulated Kinases; C094377:inhibin-alpha subunit