Distinct signalling pathways mediate the cAMP response element (CRE)-dependent activation of the calcitonin gene-related peptide gene promoter by cAMP and nerve growth factor.
The gene encoding the calcitonin gene-related peptide (CGRP) is activated in neuronal cells by treatment with cAMP and nerve growth factor (NGF). Both stimuli induce the phosphorylation of the cAMP response element (CRE)-binding protein (CREB) transcription factor on Ser-133 and require the CRE in the CGRP promoter to stimulate transcription. However, whereas the CRE is necessary and sufficient for promoter activation by cAMP, it is necessary but not sufficient for activation by NGF. We show that this difference is paralleled by a difference in the signalling pathways which are required for each stimulus to activate the CGRP promoter. Thus whilst cAMP-mediated activation requires the protein kinase A pathway, NGF-mediated stimulation requires the Ras/Raf mitogen-activated protein kinase kinase-1 (MEK-1)/p42/p44 mitogen-activated protein kinase (MAPK) pathway. Although NGF can activate the protein kinase C, p38 MAPK and c-Jun N-terminal kinase (JNK) pathways, these pathways are not involved in its effect on the CGRP promoter. The effect of the p42/p44 MAPK pathway on CREB and associated transcription factors, and the manner in which this results in activation of the CGRP promoter is discussed.
Freeland
K
K
Department of Molecular Pathology, The Windeyer Institute of Medical Sciences, University College London, The Windeyer Building, 46 Cleveland Street, London W1P 6DB, U.K.
Liu
Y Z
YZ
Latchman
D S
DS
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000096:biosynthesis / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D048669:MAP Kinase Kinase 6; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D020932:Nerve Growth Factor / Q000378:metabolism*; D016716:PC12 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D020218:Response Elements; D048051:p38 Mitogen-Activated Protein Kinases
D017362:Cyclic AMP Response Element-Binding Protein; D020932:Nerve Growth Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; D020929:Mitogen-Activated Protein Kinase Kinases; D015740:Calcitonin Gene-Related Peptide