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Articles by C. R. Mendelson
Total Records ( 3 ) for C. R. Mendelson
  D Liu , H Benlhabib and C. R. Mendelson
 

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, 5'-TGACCTTA-3') within its 5'-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.

  P Kumar , A Kamat and C. R. Mendelson
 

A 246-bp region upstream of placenta-specific exon I.1 of the human aromatase (hCYP19) gene mediates placenta-specific, developmental, and O2 regulation of expression. In this study, trophoblast differentiation and associated induction of CYP19 expression were prevented when cytotrophoblasts were cultured in phenol red-free medium containing charcoal-stripped serum or with the estrogen receptor (ER) antagonist, ICI 182,780, suggesting a stimulatory role of estrogen/ER. ER protein was expressed in human trophoblasts and increased during syncytiotrophoblast differentiation, whereas ERβ was undetectable. Mutational analysis revealed that an estrogen response element-like sequence (ERE-LS) at –208 bp is required for inductive effects of estradiol/ER on hCYP19I.1 promoter activity in transfected COS-7 cells. Increased binding of syncytiotrophoblast compared with cytotrophoblast nuclear proteins to the ERE-LS was observed in vitro; however, ER antibodies failed to supershift the complex and in vitro-transcribed/translated ER did not bind. Nonetheless, chromatin immunoprecipitation assays in cultured trophoblasts revealed recruitment of endogenous ER to the –255- to –155-bp region containing the ERE-LS before induction of hCYP19 expression; this was inhibited by ICI 182,780. Chromatin immunoprecipitation also revealed increased acetylated histone H3(K9/14) and decreased methylated histone H3(K9) associated with this region during trophoblast differentiation. These modifications were prevented when trophoblasts were incubated with ICI 182,780, suggesting that ER recruitment to the –255- to –155-bp region promotes histone modifications leading to increased hCYP19 transcription. Thus, during trophoblast differentiation, estrogen/ER exerts a positive feedback role, which promotes permissive histone modifications that are associated with induction of hCYP19 gene transcription.

  C. R. Mendelson
 

Mechanisms underlying the initiation of parturition remain unclear. Throughout most of pregnancy, uterine quiescence is maintained by elevated progesterone acting through progesterone receptor (PR). Although in most mammals, parturition is associated with a marked decline in maternal progesterone, in humans, circulating progesterone and uterine PR remain elevated throughout pregnancy, suggesting a critical role for functional PR inactivation in the initiation of labor. Both term and preterm labor in humans and rodents are associated with an inflammatory response. In preterm labor, intraamniotic infection likely provides the stimulus for increased amniotic fluid interleukins and migration of inflammatory cells into the uterus and cervix. However, at term, the stimulus for this inflammatory response is unknown. Increasing evidence suggests that the developing fetus may produce physical and hormonal signals that stimulate macrophage migration to the uterus, with release of cytokines and activation of inflammatory transcription factors, such as nuclear factor B (NF-B) and activator protein 1 (AP-1), which also is activated by myometrial stretch. We postulate that the increased inflammatory response and NF-B activation promote uterine contractility via 1) direct activation of contractile genes (e.g. COX-2, oxytocin receptor, and connexin 43) and 2) impairment of the capacity of PR to mediate uterine quiescence. PR function near term may be compromised by direct interaction with NF-B, altered expression of PR coregulators, increased metabolism of progesterone within the cervix and myometrium, and increased expression of inhibitory PR isoforms. Alternatively, we propose that uterine quiescence during pregnancy is regulated, in part, by PR antagonism of the inflammatory response.

 
 
 
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