cAMP Enhances Estrogen-Related Receptor α (ERRα) Transcriptional Activity at the SP-A Promoter by Increasing Its Interaction with Protein Kinase A and Steroid Receptor Coactivator 2 (SRC-2)

Abstract

Estrogen-related receptor (ERR␣) 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, 5Ј-TGACCTTA-3Ј) within its 5Ј-flanking region. Furthermore, protein kinase A (PKA) up-regulates ERR␣ activation of the hSP-A promoter. In the present study, using cultured human fetal lung type II cells, we observed that cAMP enhanced ERR␣ phosphorylation and nuclear expression levels. cAMP/PKA stimulation of ERR␣ 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 ERR␣ transcriptional activity. Of several coactivators tested, steroid receptor coactivator 2 (SRC-2) had the most pronounced effect to increase ERR␣ transcriptional activity at the SP-A promoter; this was enhanced by cotransfection with PKA catalytic subunit (PKAcat). Interestingly, SRC-2, ERR␣, 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 ERR␣ transcriptional activity. Collectively, these findings indicate that cAMP/PKA signaling enhances ERR␣ 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. (Molecular Endocrinology 23: 772-783, 2009)

Estrogen receptor–related receptor α regulation by interleukin‐1β in prostaglandin E2– and cAMP‐dependent pathways in osteoarthritic chondrocytes

“…The fact that the ERR␣ is regulated by cAMP is consistent with the modulation of ERR␣ observed in cells under adipogenic differentiation conditions, which include an inducer of cAMP, glucocorticoid, and insulin (38). Moreover, cAMP has been reported to increase ERR␣ protein and its transcriptional activity in lung type II cells on surfactant protein A expression, a factor that is also stimulated by IL-1␤ (39). Indeed, endogenously produced prostaglandins play an important role in promoting type II cell differentiation and induce surfactant protein A in cultured human fetal lung tissue (40).…”

Eating disorder predisposition is associated with ESRRA and HDAC4 mutations

“…Human ESRRA and mouse PGC-1α cDNAs were provided by Carol Mendelson of UT Southwestern Medical Center (48). Human HDAC4 cDNA was provided by Eric Nestler of Mount Sinai School of Medicine (New York, New York, USA) (49).…”

Steroid receptor coactivators 1 and 2 mediate fetal-to-maternal signaling that initiates parturition

“…In light of the evidence that the delayed-labor phenotype was caused by an alteration in signals produced by SRC-1/-2-deficient fetuses, as well as our previous findings that SRC-1 and SRC-2 are important for transcriptional regulation of SP-A in fetal lung type II cells (20,21), we analyzed the SP-A mRNA and protein expression in fetal lungs and secretion of SP-A protein into AF. Notably, SP-A mRNA and protein in lungs of SRC-1/-2 double-deficient fetuses were significantly decreased compared with those of WT fetuses and with those of fetuses that were singly deficient in SRC-1 or SRC-2 ( Figure 1, D and E).…”

“…hormonal regulation of expression (18,19). Steroid receptor coactivators 1 and 2, SRC-1 and SRC-2, serve important roles in transcriptional upregulation of SP-A gene expression in fetal lung type II cells (20,21). Endogenous SRC-1 in human fetal lung (HFL) type II cells was recruited with thyroid transcription factor-1 (TTF-1, also known as Nkx2.1) and NF-κB to the hSP-A promoter upon cAMP and IL-1 stimulation of SP-A expression (21,22).…”

“…Endogenous SRC-1 in human fetal lung (HFL) type II cells was recruited with thyroid transcription factor-1 (TTF-1, also known as Nkx2.1) and NF-κB to the hSP-A promoter upon cAMP and IL-1 stimulation of SP-A expression (21,22). cAMP also enhanced estrogen-related receptor α (ERRα) transcriptional activity at the SP-A promoter by increasing its interaction with protein kinase A and SRC-2 (20).…”