Mechanisms of glucocorticoid signalling.
ABSTRACT It has become increasingly clear that glucocorticoid signalling not only comprises the binding of the glucocorticoid receptor (GR) to its response element (GRE), but also involves indirect regulation glucocorticoid-responsive genes by regulating or interacting with other transcription factors. In addition, they can directly regulate gene expression by binding to negative glucocorticoid response elements (nGREs), to simple GREs, to GREs, or to GREs and GRE half sites (GRE1/2s) that are part of a regulatory unit. A response unit allows a higher level of glucocorticoid induction than simple GREs and, in addition, allows the integration of tissue-specific information with the glucocorticoid response. Presumably, the complexity of such a glucocorticoid response unit (GRU) depends on the number of pathways that integrate at this unit. Because GRUs are often located at distant sites relative to the transcription-start site, the GRU has to find a way to communicate with the basal-transcription machinery. We propose that the activating signal of a distal enhancer can be relayed onto the transcription-initiation complex by coupling elements located proximal to the promoter.
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ABSTRACT: Glucocorticoids (GCs) modulate many cellular processes through the binding of the glucocorticoid receptor (GR) to specific responsive elements located upstream of the transcription starting site or within an intron of GC target genes. Here we describe a transgenic fish line harboring a construct with nine GC-responsive elements (GREs) upstream of a reporter (EGFP) coding sequence. Transgenic fish exhibit strong fluorescence in many known GC-responsive organs. Moreover, its enhanced sensitivity allowed the discovery of novel GC-responsive tissue compartments, such as fin, eyes, and otic vesicles. Long-term persistence of transgene expression is seen during adult stages in several organs. Pharmacological and genetic analysis demonstrates that the transgenic line is highly responsive to drug administration and molecular manipulation. Moreover, reporter expression is sensitively and dynamically modulated by the photoperiod, thus proving that these fish are an in vivo valuable platform to explore GC responsiveness to both endogenous and exogenous stimuli.Molecular and Cellular Endocrinology 05/2014; · 4.04 Impact Factor
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ABSTRACT: Pseudomyxoma peritonei (PMP, ORPHA26790) is a clinical syndrome characterized by progressive dissemination of mucinous tumors and mucinous ascites in the abdomen and pelvis. PMP is a rare disease with an estimated incidence of 1–2 out of a million. Clinically, PMP usually presents with a variety of unspecific signs and symptoms, including abdominal pain and distention, ascites or even bowel obstruction. It is also diagnosed incidentally at surgical or non-surgical investigations of the abdominopelvic viscera. PMP is a neoplastic disease originating from a primary mucinous tumor of the appendix with a distinctive pattern of the peritoneal spread. Computed tomography and histopathology are the most reliable diagnostic modalities. The differential diagnosis of the disease includes secondary peritoneal carcinomatoses and some rare peritoneal conditions. Optimal elimination of mucin and the mucin-secreting tumor comprises the current standard of care for PMP offered in specialized centers as visceral resections and peritonectomy combined with intraperitoneal chemotherapy. This multidisciplinary approach has reportedly provided a median survival rate of 16.3 years, a median progression-free survival rate of 8.2 years and 10- and 15-year survival rates of 63% and 59%, respectively. Despite its indolent, bland nature as a neoplasm, PMP is a debilitating condition that severely impacts quality of life. It tends to be diagnosed at advanced stages and frequently recurs after treatment. Being ignored in research, however, PMP remains a challenging, enigmatic entity. Clinicopathological features of the PMP syndrome and its morbid complications closely correspond with the multi focal distribution of the secreted mucin collections and mucin-secreting implants. Novel strategies are thus required to facilitate macroscopic, as well as microscopic, eliminati on of mucin and its source as the key components of the disease. In this regard, MUC2, MUC5AC and MUC5B have been found as the secreted mucins of relevance in PMP. Development of mucin-targeted therapies could be a promising avenue for future research which is addressed in this article.Orphanet Journal of Rare Diseases 05/2014; · 4.32 Impact Factor
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ABSTRACT: Glucocorticoids (GCs) strongly regulate myostatin transcript levels in mammals via glucocorticoid response elements (GREs) in the myostatin promoter, and bioinformatics methods suggest that this regulatory mechanism is conserved among many vertebrates. However, the multiple myostatin genes found in some fishes may be an exception. In rainbow trout (Oncorhynchus mykiss), two genome duplication events have produced three putatively functional myostatin genes, myostatin-1a, -1b and -2a, which are ubiquitously and differentially expressed. In addition, in silico promoter analyses of the rainbow trout myostatin promoters have failed to identify putative GREs, suggesting a divergence in myostatin function. Therefore, we hypothesized that myostatin mRNA expression is not regulated by glucocorticoids in rainbow trout. In this study, both juvenile rainbow trout and primary trout myoblasts were treated with cortisol to examine the relationship between this glucocorticoid and myostatin mRNA expression. Results suggest that exogenous cortisol does not regulate myostatin-1a and -1b expression in vivo, as myostatin mRNA levels were not significantly affected by cortisol treatment in either red or white muscle tissue. In red muscle, myostatin-2a levels were significantly elevated in the cortisol treatment group relative to the control, but not the vehicle control, at both 12h and 24h post-injection. As such, it is unclear if cortisol was acting alone or in combination with the vehicle. Cortisol increased myostatin-1b expression in a dose-dependent manner in vitro. Further work is needed to determine if this response is the direct result of cortisol acting on the myostatin-1b promoter or through an alternative mechanism. These results suggest that regulation of myostatin by cortisol may not be as highly conserved as previously thought and support previous work that describes potential functional divergence of the multiple myostatin genes in fishes.Comparative biochemistry and physiology. Part A, Molecular & integrative physiology. 05/2014;