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Kumar R.,The Commonwealth Medical College | McEwan I.J.,University of Aberdeen
Endocrine Reviews | Year: 2012

Steroid hormones are synthesized from cholesterol primarily in the adrenal glandandthe gonadsandplay vital roles in normal physiology, the control of development, differentiation, metabolic homeostasis, and reproduction. The actions of these small lipophilic molecules are mediated by intracellular receptor proteins. It is just over 25 yr since the first cDNA for steroid receptors were cloned, a development that led to the birth of a superfamily of ligandactivated transcription factors: the nuclear receptors. The receptor proteins share structurally and functionally related ligand binding and DNA-binding domains but possess distinct N-terminal domains and hinge regions that are intrinsically disordered. Since the original cloning experiments, considerable progress has been made in our understanding of the structure, mechanisms of action, and biology of this important class of ligand-activated transcription factors. In recent years, there has been interest in the structural plasticity and function of the N-terminal domain of steroid hormone receptors and in the allosteric regulation of protein folding and function in response to hormone, DNAresponse element architecture, and coregulatory protein binding partners. The N-terminal domain can exist as an ensemble of conformers, havingmoreor less structure, which prime this region of the receptor to rapidly respond to changes in the intracellular environment through hormone binding and posttranslation modifications. In this review, we address the question of receptor structure and function dynamics with particular emphasis on the structurally flexible N-terminal domain, intra- and interdomain communications, and the allosteric regulation of receptor action. © 2012 by The Endocrine Society. Source


Kumar R.,The Commonwealth Medical College | Thompson E.B.,University of Texas Medical Branch
Archives of Biochemistry and Biophysics | Year: 2010

Despite their importance in gene regulation, the exact mechanisms of glucocorticoid receptor's (GR's) N-terminal activation function region, AF1, which exists in an intrinsically disordered (ID) conformation remains largely unknown. For its interaction with critical coregulatory proteins, AF1 must be malleable and capable of presenting varied interaction surfaces. We hypothesize that various confluences of effects, including intra-molecular signaling between the AF1 and the GR DNA-binding domain (DBD) cause functional structure to form in AF1. In this study, we tested the effect of the amino acid sequences surrounding AF1 on the propensity of AF1 to gain structure when connected to DBD. Removal of amino acids between AF1 and DBD results in the formation of more ordered conformation in AF1. In addition, sequences flanking the AF1 may play an inhibitory role in AF1 activity. These results suggest a mechanism as to why certain GR isoforms with truncated N-terminal domains show altered transcriptional activity. © 2010 Elsevier Inc. Source


Shantha G.P.S.,The Wright Center for Graduate Medical Education | Pancholy S.B.,The Wright Center for Graduate Medical Education | Pancholy S.B.,The Commonwealth Medical College
Sleep and Breathing | Year: 2015

Purpose: Recent evidence associates sympathetic tone with severity of obstructive sleep apnea (OSA). Renal sympathetic denervation (RDN), by decreasing sympathetic tone, has the potential to decrease OSA severity. Small observational studies that assessed this hypothesis lacked precision. Hence, in this meta-analysis, we have attempted to pool available data from studies that have assessed the effect of RDN on OSA severity in patients with OSA. Methods: Medline, Embase, Cochrane central, Ovid, Cinahl, web of science, and conference abstracts were searched for eligible citations by two independent reviewers using key words “renal denervation,” “hypertension,” and “obstructive sleep apnea.” From a total of 2,863 identified citations, using meta-analysis of observational studies in epidemiology method, five studies were assessed eligible and included in the meta-analysis. Results: All five studies followed an observational study design, involved patients with OSA and HTN, and reported an apnea-hypopnea index (AHI) 6 months post-RDN. Four were “before and after” studies and one compared continuous positive airway pressure with RDN. In the pooled analysis, involving 49 patients, RDN was associated with a significant reduction in mean AHI [weighted mean difference −9.61 (95 % CI −15.43 to −3.79, P = 0.001)] 6 months post-RDN. One study also reported improvement in oxygen desaturation index and Epworth sleepiness scale score 6 months post-RDN. Conclusions: RDN is associated with significant improvement in OSA severity. However, our results need validation in RCTs that assess effect of RDN in patients with OSA, which can potentially broaden the clinical applicability of RDN. © 2014, Springer-Verlag Berlin Heidelberg. Source


Bordonaro M.,The Commonwealth Medical College
Journal of Cancer | Year: 2013

RNA processing involves a variety of processes affecting gene expression, including the removal of introns through RNA splicing, as well as 3' end processing (cleavage and polyadenylation). Alternative RNA processing is fundamentally important for gene regulation, and aberrant processing is associated with the initiation and progression of cancer. Deregulated Wnt signaling, which is the initiating event in the development of most cases of human colorectal cancer (CRC), has been linked to modified RNA processing, which may contribute to Wnt-mediated colonic carcinogenesis. Crosstalk between Wnt signaling and alternative RNA splicing with relevance to CRC includes effects on the expression of Rac1b, an alternatively spliced gene associated with tumorigenesis, which exhibits alternative RNA splicing that is influenced by Wnt activity. In addition, Tcf4, a crucial component of Wnt signaling, also exhibits alternative splicing, which is likely involved in colonic tumorigenesis. Modulation of 3' end formation, including of the Wnt target gene COX-2, also can influence the neoplastic process, with implications for CRC. While many human genes are dependent on introns and splicing for normal levels of gene expression, naturally intronless genes exist with a unique metabolism that allows for intron-independent gene expression. Effects of Wnt activity on the RNA metabolism of the intronless Wnt-target gene c-jun is a likely contributor to cancer development. Further, butyrate, a breakdown product of dietary fiber and a histone deacetylase inhibitor, upregulates Wnt activity in CRC cells, and also modulates RNA processing; therefore, the interplay between Wnt activity, the modulation of this activity by butyrate, and differential RNA metabolism in colonic cells can significantly influence tumorigenesis. Determining the role played by altered RNA processing in Wnt-mediated neoplasia may lead to novel interventions aimed at restoring normal RNA metabolism for therapeutic benefit. Therefore, this minireview presents a brief overview of several aspects of RNA processing of relevance to cancer, which potentially influence, or are influenced by, Wnt signaling activity. © Ivyspring International Publisher. Source


Simons S.S.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Edwards D.P.,Baylor College of Medicine | Kumar R.,The Commonwealth Medical College
Molecular Endocrinology | Year: 2014

Therapeutic targeting of nuclear receptors (NRs) is presently restricted due to 2 constraints: 1) a limited knowledge of the structural dynamics of intact receptor when complexed to DNA and coregulatory proteins; and 2) the inability to more selectively modulate NR actions at specific organ/gene targets. A major obstacle has been the current lack of understanding about the function and structure of the intrinsically disordered N-terminal domain that contains a major regulatory transcriptional activation function (AF1). Current studies of both mechanism of action and small molecule-selective receptor modulators for clinical uses target the structured pocket of the ligand-binding domain to modulate coregulatory protein interactions with the other activation function AF2. However, these approaches overlook AF1 activity. Recent studies have shown that highly flexible intrinsically disordered regions of transcription factors, including that of the N-terminal domain AF1 of NRs, not only are critical for several aspects of NR action but also can be exploited as drug targets, thereby opening unique opportunities for endocrine-based therapies. In this review article, we discuss the role of structural flexibilities in the allosteric modulation of NR activity and future perspectives for therapeutic interventions. © 2014 by the Endocrine Society. Source

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