Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells.
Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-RP). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.
Steinmetz
R
R
Section of Pediatric Endocrinology/Diabetology, Wells Center for Pediatric Research, Department of Pediatrics, Physiology and Biophysics, Indiana University School of Medicine, Indianapolis, USA. rsteinme@iupui.edu
Zeng
P
P
King
D W
DW
Walvoord
E
E
Pescovitz
O H
OH
D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000494:pharmacology; D004268:DNA-Binding Proteins; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D013007:Growth Hormone-Releasing Hormone / Q000737:chemistry / Q000494:pharmacology*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation; D010902:Pituitary Gland / Q000201:enzymology*; D011401:Promoter Regions, Genetic; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011498:Protein Precursors / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D048051:p38 Mitogen-Activated Protein Kinases
D022762:CCAAT-Enhancer-Binding Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004268:DNA-Binding Proteins; C497251:Ddit3 protein, rat; C494114:Elk1 protein, rat; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D011498:Protein Precursors; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; C099166:growth hormone releasing hormone-related peptide; D051742:Transcription Factor CHOP; D013007:Growth Hormone-Releasing Hormone; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases