Growth hormone stimulates phosphorylation and activation of elk-1 and expression of c-fos, egr-1, and junB through activation of extracellular signal-regulated kinases 1 and 2.
Growth hormone (GH), a major regulator of normal body growth and metabolism, regulates cellular gene expression. The transcription factors Elk-1 and Serum Response Factor are necessary for GH-stimulated transcription of c-fos through the Serum Response Element (SRE). GH stimulates the serine phosphorylation of Elk-1, thereby enabling Elk-1 to mediate transcriptional activation. The contribution of the Ras/mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway to Elk-1-mediated transcriptional activation of the c-fos SRE in response to GH was examined. The MEK inhibitor PD098059 attenuated GH-induced expression of the endogenous SRE-regulated genes c-fos, egr-1, and junB as well as transcriptional activation mediated by the c-fos promoter. The MEK inhibitor blocked GH-stimulated activation of MEK, phosphorylation of ERK1/ERK2, and MAP kinase activity in 3T3-F442A cells. Blocking MEK activation prevented GH-induced phosphorylation of Elk-1, as well as the ability of Elk-1 to mediate transcriptional activation in response to GH. Overexpression of dominant-negative Ras or the ERK-specific phosphatase, mitogen-activated protein kinase phosphatase-1, blocked the Ras/MEK/ERK pathway and abrogated GH-induced phosphorylation of Elk-1. GH failed to stimulate phosphorylation or activation of Jun N-terminal kinase under the conditions used. GH slightly increased p38-mediated mitogen-activated protein kinase-activated protein (MAPKAP) kinase-2 activity, but the p38 inhibitor SB203580 did not attenuate GH-promoted Elk-1 phosphorylation. Wortmannin, which inhibited GH-induced ERK phosphorylation, also attenuated transcriptional activation of c-fos by GH. Taken together, these data suggest that GH-dependent activation of the Ras/MEK/ERK pathway and subsequent serine phosphorylation of Elk-1 contribute to GH-stimulated c-fos expression through the SRE.
Hodge
C
C
Program in Cellular and Molecular Biology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0622, USA.
Liao
J
J
Stofega
M
M
Guan
K
K
Carter-Su
C
C
Schwartz
J
J
D016475:3T3 Cells; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D051766:Early Growth Response Protein 1; D005419:Flavonoids / Q000494:pharmacology; D013006:Growth Hormone / Q000494:pharmacology*; D017874:Immediate-Early Proteins; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D000077191:Wortmannin; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins / Q000378:metabolism
D000730:Androstadienes; D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C494113:Elk1 protein, mouse; D005419:Flavonoids; D017874:Immediate-Early Proteins; D011518:Proto-Oncogene Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D013006:Growth Hormone; D019869:Phosphatidylinositol 3-Kinases; D020794:Receptor Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D018631:ras Proteins; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000077191:Wortmannin