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PMID: 19264843 Published · ppublish English Journal Article Research Support, N.I.H., Extramural

cAMP enhances estrogen-related receptor alpha (ERRalpha) transcriptional activity at the SP-A promoter by increasing its interaction with protein kinase A and steroid receptor coactivator 2 (SRC-2).

Molecular endocrinology (Baltimore, Md.) ·Vol. 23 ·No. 6 ·2009-06-00 ·Pages 772-83

Liu D, Benlhabib H, Mendelson CR

Abstract

Estrogen-related receptor (ERRalpha) plays a critical role in basal and cAMP-induced expression of the human surfactant protein-A (SP-A) gene in lung type II cells through direct binding to an ERR response element (ERRE, 5'-TGACCTTA-3') within its 5'-flanking region. Furthermore, protein kinase A (PKA) up-regulates ERRalpha activation of the hSP-A promoter. In the present study, using cultured human fetal lung type II cells, we observed that cAMP enhanced ERRalpha phosphorylation and nuclear expression levels. cAMP/PKA stimulation of ERRalpha activation of the SP-A promoter was blocked by the PKA inhibitor, H89, whereas the MAPK P38 inhibitor, SB203580, and the MAPK kinase inhibitor, PD98059, had negligible to modest effects. This suggests that cAMP acts selectively through PKA to increase ERRalpha transcriptional activity. Of several coactivators tested, steroid receptor coactivator 2 (SRC-2) had the most pronounced effect to increase ERRalpha transcriptional activity at the SP-A promoter; this was enhanced by cotransfection with PKA catalytic subunit (PKAcat). Interestingly, SRC-2, ERRalpha, and PKAcat in type II cell nuclear extracts interacted at the ERRE; this was enhanced by cAMP and inhibited by H89. cAMP increased in vivo binding of PKAcat and SRC-2 to the ERRE genomic region in lung type II cells. In mutagenesis studies, three serines (S87, S114, and S277) were found to be critical for PKA and SRC-2 induction of ERRalpha transcriptional activity. Collectively, these findings indicate that cAMP/PKA signaling enhances ERRalpha phosphorylation and nuclear localization, recruitment to the SP-A promoter, and interaction with PKAcat and SRC-2, resulting in the up-regulation of SP-A gene transcription.

MeSH Terms
Animals Cell Nucleus/drug effects,metabolism Cyclic AMP/pharmacology Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors,metabolism Enzyme Activation/drug effects Fetus/cytology Genome, Human/genetics Humans Isoquinolines/pharmacology Lung/cytology Mice Nuclear Receptor Coactivator 2/metabolism Phosphorylation/drug effects Promoter Regions, Genetic/genetics Protein Binding/drug effects Protein Transport/drug effects Pulmonary Surfactant-Associated Protein A/genetics,metabolism Receptors, Estrogen/genetics,metabolism Response Elements/genetics Serine/metabolism Sulfonamides/pharmacology Threonine/metabolism Transcription, Genetic/drug effects
Chemicals
ERRalpha estrogen-related receptor Isoquinolines Nuclear Receptor Coactivator 2 Pulmonary Surfactant-Associated Protein A Receptors, Estrogen Sulfonamides Threonine Serine Cyclic AMP Cyclic AMP-Dependent Protein Kinases N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Liu Dongyuan
Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 75390-9038, USA.
Benlhabib Houda
Mendelson Carole R
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Article Info
Journal
Molecular endocrinology (Baltimore, Md.)
Abbr.
Mol Endocrinol
ISSN
1944-9917
DOI
10.1210/me.2008-0282
Published
2009-06-00
Epub
2009-00-05
Pages
772-83
Language
English
Region
United States
NLM ID
8801431
PMCID
PMC2691680
Subset
IM
Grants
NHLBI NIH HHS · R37 HL050022 · United States
External Links
PubMed source DOI: 10.1210/me.2008-0282 PMC Full Text
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