Apoptosis is a conserved homeostatic process critical for organ and tissue morphogenesis, development, and senescence. This form of programmed cell death also participates in the etiology of several ...human diseases including cancer, neurodegenerative, and autoimmune disorders. Although the signaling pathways leading to the progression of apoptosis have been extensively characterized, recent studies highlight the regulatory role of changes in the intracellular milieu (permissive apoptotic environment) in the efficient activation of the cell death machinery. In particular, glutathione (GSH) depletion is a common feature of apoptotic cell death triggered by a wide variety of stimuli including activation of death receptors, stress, environmental agents, and cytotoxic drugs. Although initial studies suggested that GSH depletion was only a byproduct of oxidative stress generated during cell death, recent discoveries suggest that GSH depletion and post-translational modifications of proteins through glutathionylation are critical regulators of apoptosis. Here, we reformulate these emerging paradigms into our current understanding of cell death mechanisms.
Immune regulation by glucocorticoids Cain, Derek W; Cidlowski, John A
Nature reviews. Immunology,
04/2017, Letnik:
17, Številka:
4
Journal Article
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Endogenous glucocorticoids are crucial to various physiological processes, including metabolism, development and inflammation. Since 1948, synthetic glucocorticoids have been used to treat various ...immune-related disorders. The mechanisms that underlie the immunosuppressive properties of these hormones have been intensely scrutinized, and it is widely appreciated that glucocorticoids have pleiotropic effects on the immune system. However, a clear picture of the cellular and molecular basis of glucocorticoid action has remained elusive. In this Review, we distil several decades of intense (and often conflicting) research that defines the interface between the endocrine stress response and the immune system.
Glucocorticoids are among the most common therapeutic agents used in medical practice, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how ...glucocorticoids inhibit inflammation and give rise to side effects.
Glucocorticoids are common therapeutic agents, yet their mechanisms of action are only partly understood. This review summarizes our understanding of how glucocorticoids inhibit inflammation and give rise to side effects.
Inflammation is a reflexive response to infection, the binding of antibodies to antigens within the body, mechanical irritation, or injury.
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Microbes that breach epithelial barriers, for instance, directly activate complement and toll-like receptors, two principal components of the innate immune system. The activation of these sentinels triggers the synthesis and release of inflammatory mediators with acute effects on the vasculature. Localized vasodilation, increased vascular permeability, extravasation of plasma (and humoral) proteins, and migration of leukocytes into the affected tissue produce the classic signs of inflammation: calor, dolor, rubor, tumor, and functio laesa. A positive feedback loop initiates the production of . . .
Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is ...generally referred to as 'accidental cell death' (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. 'Regulated cell death' (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death.
ErbB-2 amplification/overexpression accounts for an aggressive breast cancer (BC) subtype (ErbB-2-positive). Enhanced ErbB-2 expression was also found in gastric cancer (GC) and has been correlated ...with poor clinical outcome. The ErbB-2-targeted therapies trastuzumab (TZ), a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, have proved highly beneficial. However, resistance to such therapies remains a major clinical challenge. We here revealed a novel mechanism underlying the antiproliferative effects of both agents in ErbB-2-positive BC and GC. TZ and lapatinib ability to block extracellular signal-regulated kinases 1/2 and phosphatidylinositol-3 kinase (PI3K)/AKT in sensitive cells inhibits c-Myc activation, which results in upregulation of miR-16. Forced expression of miR-16 inhibited in vitro proliferation in BC and GC cells, both sensitive and resistant to TZ and lapatinib, as well as in a preclinical BC model resistant to these agents. This reveals miR-16 role as tumor suppressor in ErbB-2-positive BC and GC. Using genome-wide expression studies and miRNA target prediction algorithms, we identified cyclin J and far upstream element-binding protein 1 (FUBP1) as novel miR-16 targets, which mediate miR-16 antiproliferative effects. Supporting the clinical relevance of our results, we found that high levels of miR-16 and low or null FUBP1 expression correlate with TZ response in ErbB-2-positive primary BCs. These findings highlight a potential role of miR-16 and FUBP1 as biomarkers of sensitivity to TZ therapy. Furthermore, we revealed miR-16 as an innovative therapeutic agent for TZ- and lapatinib-resistant ErbB-2-positive BC and GC.
Glucocorticoids are a vital class of endogenous steroid hormones that regulate essential biological processes including growth, development, metabolism, behavior and apoptosis. Most, if not all, of ...these actions are thought to be mediated through the glucocorticoid receptor. The exact mechanisms of how one hormone, via one receptor, modulates such diverse biological functions are largely unknown. However, recent studies from our lab and others have suggested that a contribution for the diversity results from multiple isoforms of the glucocorticoid receptor that result from alternative RNA splicing and translation initiation of the glucocorticoid receptor mRNA. Additionally, each isoform is subject to several post-translational modifications, including phosphorylation, ubiquitination and sumoylation, which have been shown to modulate the receptor protein stability and/or function. Together these data provide potentially diverse mechanisms to establish cell type specific regulation of gene expression by a single transcription factor. Here, we summarize the recent advances and processes that generate these receptor isoforms and these post-translational modifications. We speculate that the composition and proportion of individual isoforms expressed in particular cellular contexts account for the diverse effects of glucocorticoid hormones.
Ligand-dependent down-regulation of the glucocorticoid receptor (GR) has been shown to limit hormone responsiveness, but the
mechanisms involved in this process are poorly understood. The ...glucocorticoid receptor is a phosphoprotein that upon ligand
binding becomes hyperphosphorylated, and recent evidence indicates that phosphorylation status of the glucocorticoid receptor
plays a prominent role in receptor protein turnover. Because phosphorylation is a key signal for ubiquitination and proteasomal
catabolism of many proteins, we evaluated whether the ubiquitin-proteasomal pathway had a role in glucocorticoid receptor
down-regulation and the subsequent transcriptional response to glucocorticoids. Pretreatment of COS-1 cells expressing mouse
glucocorticoid receptor with the proteasome inhibitor MG-132 effectively blocks glucocorticoid receptor protein down-regulation
by the glucocorticoid dexamethasone. Interestingly, both MG-132 and a second proteasome inhibitor β-lactone significantly
enhanced hormone response of transfected mouse glucocorticoid receptor toward transcriptional activation of glucocorticoid
receptor-mediated reporter gene expression. The transcriptional activity of the endogenous human glucocorticoid receptor in
HeLa cells was also enhanced by MG-132. Direct evidence for ubiquitination of the glucocorticoid receptor was obtained by
immunoprecipitation of cellular extracts from proteasome-impaired cells. Examination of the primary sequence of mouse, human,
and rat glucocorticoid receptor has identified a candidate PEST degradation motif. Mutation of Lys-426 within this PEST element
both abrogated ligand-dependent down-regulation of glucocorticoid receptor protein and simultaneously enhanced glucocorticoid
receptor-induced transcriptional activation of gene expression. Unlike wild type GR, proteasomal inhibition failed to enhance
significantly transcriptional activity of K426A mutant GR. Together these findings suggest a major role of the ubiquitin-proteasome
pathway in regulating glucocorticoid receptor protein turnover, thereby providing a mechanism to terminate glucocorticoid
responses.
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