The inhibitor of apoptosis proteins (IAPs) are best known for their ability to regulate cell survival and death processes. However, in addition to cell death, IAPs also act as innate immune sensors and modulate multiple pathways, such as autophagy and cell division. Many of these IAP functions are non-redundant even though they are based on the same molecular mechanism of action. These distinct functions of IAPs derive from their capacity to target specific substrates for ubiquitination and/or proteolytic cleavage. The unique functions of IAPs also derives from their unique cellular localizations, cell type and tissue-specific expression patterns. The diverse roles of IAPs are reflected by the fact that in humans the IAP family comprises eight distinct members. Genetic evidence from human pathologies also attests to the non-redundant functions of the IAPs since very diverse diseases arise upon aberrant IAP expression. In this review, we give an overview of the known mechanisms of action of the various IAPs, and focus on their specific roles in mediating innate immunity. We also look at the distinct phenotypes related to the dysregulation of the IAPs, and the human pathologies associated with each human IAP.

• MeSH
• autoimunitní nemoci imunologie   patologie   MeSH
• buněčná smrt MeSH
• infekce imunologie   patologie   MeSH
• inflamasomy imunologie   MeSH
• inhibitory apoptózy genetika   imunologie   MeSH
• lidé MeSH
• signální transdukce MeSH
• viabilita buněk * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• inflamasomy MeSH
• inhibitory apoptózy MeSH

Survivin, an important antiapoptotic protein, is expressed in tumors, whereas in normal tissues the expression of this protein is extremely low, defining a role for survivin as a cancer gene. Survivin exhibits multifunctional activity in tumor cells. However, why survivin expression is sharply and invariably restricted to tumor tissue remains unclear. Here, we identified 11 putative consensus binding sites for GLI transcription factors in the survivin promoter and characterized the promoter activity. Inhibitors of the Hedgehog/GLI pathway, cyclopamine and GANT61, decreased the promoter activity in reporter assays. ΔNGLI2 (which lacks the repressor domain) was the most potent vector in activating the survivin promoter-reporter. Moreover, GANT61, a GLI1/2 inhibitor, repressed endogenous survivin protein and mRNA expression in most cells across a large panel of tumor cell lines. Chromatin immunoprecipitation showed GLI2 binding to the survivin promoter. The ectopic GLI2-evoked expression of endogenous survivin was observed in normal human fibroblasts. GANT61 decreased survivin level in nude mice tumors, mimicking the activity of GANT61 in cultured cells. The immunohistochemistry and double immunofluorescence of human tumors revealed a correlation between the tissue regions showing high GLI2 and survivin positivity. Thus, these results demonstrated that survivin is a classical transcriptional target of GLI2, a Hedgehog pathway signaling effector. This potentially reflects the high expression of survivin in human tumor cells. As the Hedgehog pathway is upregulated in virtually all types of cancer cells, these findings substantially contribute to the explanation of uniform survivin expression in tumors as a potential target for the development of a more effective treatment of cancers through the inhibition of GLI2 to restrain survivin activity.

• MeSH
• inhibitory apoptózy genetika   metabolismus   MeSH
• lidé MeSH
• myši nahé MeSH
• myši MeSH
• proteiny hedgehog metabolismus   MeSH
• represorové proteiny genetika   metabolismus   MeSH
• signální transdukce MeSH
• survivin MeSH
• transfekce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Birc5 protein, mouse MeSH Prohlížeč
• inhibitory apoptózy MeSH
• proteiny hedgehog MeSH
• represorové proteiny MeSH
• survivin MeSH

Inhibition of apoptosis by the ligands of the aryl hydrocarbon receptor (AhR) has been proposed to play a role in their tumor promoting effects on liver parenchymal cells. However, little is presently known about the impact of toxic AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on apoptosis in other liver cell types, such as in liver epithelial/progenitor cells. In the present study, we focused on the effects of TCDD on apoptosis regulation in a model of liver progenitor cells, rat WB-F344 cell line, during the TCDD-elicited release from contact inhibition. The stimulation of cell proliferation in this cell line was associated with deregulated expression of a number of genes known to be under transcriptional control of the Hippo signaling pathway, a principal regulatory pathway involved in contact inhibition of cell proliferation. Interestingly, we found that mRNA and protein levels of survivin, a known Hippo target, which plays a role both in cell division and inhibition of apoptosis, were significantly up-regulated in rat liver epithelial cell model, as well as in undifferentiated human liver HepaRG cells. Using the short interfering RNA-mediated knockdown, we confirmed that survivin plays a central role in cell division of WB-F344 cells. When evaluating the effects of TCDD on apoptosis induction by camptothecin, a genotoxic topoisomerase I inhibitor, we observed that the pre-treatment of WB-F344 cells with TCDD increased number of cells with apoptotic nuclear morphology, and it potentiated cleavage of both caspase-3 and poly(ADP-ribose) polymerase I. This indicated that despite the observed up-regulation of survivin, apoptosis induced by the genotoxin was potentiated in the model of rat liver progenitor cells. The present results indicate that, unlike in hepatocytes, AhR agonists may not prevent induction of apoptosis elicited by DNA-damaging agents in a model of rat liver progenitor cells.

• Klíčová slova
• AhR, Apoptosis, BIRC5/survivin, Contact inhibition, Hippo signaling, TCDD,
• MeSH
• apoptóza účinky léků   MeSH
• buněčné linie MeSH
• časové faktory MeSH
• epitelové buňky účinky léků   metabolismus   patologie   MeSH
• genetická transkripce účinky léků   MeSH
• inhibitory apoptózy genetika   metabolismus   MeSH
• inhibitory topoisomerasy I toxicita   MeSH
• játra účinky léků   metabolismus   patologie   MeSH
• kamptothecin toxicita   MeSH
• kaspasa 3 metabolismus   MeSH
• kontaktní inhibice účinky léků   MeSH
• lidé MeSH
• poly(ADP-ribosa)polymerasa 1 MeSH
• poly(ADP-ribosa)polymerasy metabolismus   MeSH
• polychlorované dibenzodioxiny toxicita   MeSH
• potkani inbrední F344 MeSH
• proteiny asociované s mikrotubuly genetika   metabolismus   MeSH
• receptory aromatických uhlovodíků agonisté   metabolismus   MeSH
• RNA interference MeSH
• signální transdukce účinky léků   MeSH
• survivin MeSH
• transfekce MeSH
• transkripční faktory bHLH agonisté   metabolismus   MeSH
• upregulace MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• Ahr protein, rat MeSH Prohlížeč
• BIRC5 protein, human MeSH Prohlížeč
• Birc5 protein, rat MeSH Prohlížeč
• Casp3 protein, rat MeSH Prohlížeč
• inhibitory apoptózy MeSH
• inhibitory topoisomerasy I MeSH
• kamptothecin MeSH
• kaspasa 3 MeSH
• Parp1 protein, rat MeSH Prohlížeč
• poly(ADP-ribosa)polymerasa 1 MeSH
• poly(ADP-ribosa)polymerasy MeSH
• polychlorované dibenzodioxiny MeSH
• proteiny asociované s mikrotubuly MeSH
• receptory aromatických uhlovodíků MeSH
• survivin MeSH
• transkripční faktory bHLH MeSH

Deletion of the cellular inhibitor of apoptosis protein 2 (cIAP2) is capable of rendering lipopolysaccharide (LPS)-activated macrophages highly susceptible to apoptotic triggers, thereby quickly eliminating the resident macrophage population soon after the initiation of a systemic inflammatory response. The aim of our study was to evaluate the impact of cIAP2 deletion on leukocyte recruitment and capillary perfusion in experimental endotoxemia and polybacterial sepsis using intravital microscopy of the intestinal microcirculation, which is crucial in the pathogenesis of septic multiple organ failure. We studied six groups of animals: wild-type (WT) control mice, cIAP2 knockout mice, endotoxemic WT mice (5 mg/kg LPS), endotoxemic cIAP2 knockouts (5 or 50 mg/kg LPS, respectively), and WT as well as knockout mice with polybacterial sepsis (colon ascendens stent peritonitis [CASP]). Intravital microscopy of the intestinal microcirculation was performed after 1 h of endotoxemia or 12 h of CASP-induced sepsis, respectively. Intestinal microvascular blood flow was measured using laser Doppler flowmetry. After 1 h of endotoxemia (5 mg/kg LPS), we observed a significant increase of leukocyte adhesion in intestinal submucosal venules of WT mice in comparison with control animals. The cIAP2 knockout mice showed a significant reduction in leukocyte recruitment within the intestinal submucosal microvasculature after 5 or 50 mg/kg LPS challenge, respectively. Lipopolysaccharide-induced decrease in intestinal microvascular blood flow was not affected by cIAP2 inhibition. In CASP-induced sepsis, cIAP2 deletion had no effect on intestinal leukocyte recruitment. Deletion of cIAP2 resulted in reduced microvascular leukocyte recruitment within the intestinal microcirculation in endotoxemia but not in polybacterial sepsis.

• MeSH
• endotoxemie genetika   metabolismus   patofyziologie   MeSH
• inhibitory apoptózy genetika   metabolismus   MeSH
• mikrocirkulace genetika   fyziologie   MeSH
• modely nemocí na zvířatech MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• sepse genetika   metabolismus   patofyziologie   MeSH
• střeva krevní zásobení   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• inhibitory apoptózy MeSH

Metastasized malignant melanoma has a poor prognosis because of its intrinsic resistance to chemotherapy and radiotherapy. The central role in the melanoma transcriptional network has the transcription factor MITF (microphthalmia-associated transcription factor). It has been shown recently that the expression of MITF and some of its target genes require the SWI/SNF chromatin remodeling complex. Here we demonstrate that survival of melanoma cells requires functional SWI/SNF complex not only by supporting expression of MITF and its targets and but also by activating expression of prosurvival proteins not directly regulated by MITF. Microarray analysis revealed that besides the MITF-driven genes, expression of proteins like osteopontin, IGF1, TGFß2 and survivin, the factors known to be generally associated with progression of tumors and the antiapoptotic properties, were reduced in acute BRG1-depleted 501mel cells. Western blots and RT-PCR confirmed the microarray findings. These proteins have been verified to be expressed independently of MITF, because MITF depletion did not impair their expression. Because these genes are not regulated by MITF, the data suggests that loss of BRG1-based SWI/SNF complexes negatively affects survival pathways beyond the MITF cascade. Immunohistochemistry showed high expression of both BRM and BRG1 in primary melanomas. Exogenous CDK2, osteopontin, or IGF1 each alone partly relieved the block of proliferation imposed by BRG1 depletion, implicating that more factors, besides the MITF target genes, are involved in melanoma cell survival. Together these results demonstrate an essential role of SWI/SNF for the expression of MITF-dependent and MITF-independent prosurvival factors in melanoma cells and suggest that SWI/SNF may be a potential and effective target in melanoma therapy.

• MeSH
• apoptóza genetika   MeSH
• chromozomální proteiny, nehistonové genetika   metabolismus   MeSH
• cyklin-dependentní kinasa 2 genetika   metabolismus   MeSH
• DNA-helikasy genetika   metabolismus   MeSH
• imunohistochemie MeSH
• inhibitory apoptózy genetika   metabolismus   MeSH
• insulinu podobný růstový faktor I genetika   metabolismus   MeSH
• jaderné proteiny genetika   metabolismus   MeSH
• lidé MeSH
• melanom genetika   metabolismus   patologie   MeSH
• nádorové buněčné linie MeSH
• névus genetika   metabolismus   patologie   MeSH
• osteopontin genetika   metabolismus   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• proliferace buněk MeSH
• RNA interference MeSH
• sekvenční analýza hybridizací s uspořádaným souborem oligonukleotidů MeSH
• stanovení celkové genové exprese MeSH
• survivin MeSH
• transformující růstový faktor beta2 genetika   metabolismus   MeSH
• transkripční faktor spojený s mikroftalmií genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• viabilita buněk genetika   MeSH
• western blotting MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• BIRC5 protein, human MeSH Prohlížeč
• CDK2 protein, human MeSH Prohlížeč
• chromozomální proteiny, nehistonové MeSH
• cyklin-dependentní kinasa 2 MeSH
• DNA-helikasy MeSH
• inhibitory apoptózy MeSH
• insulinu podobný růstový faktor I MeSH
• jaderné proteiny MeSH
• MITF protein, human MeSH Prohlížeč
• osteopontin MeSH
• SMARCA2 protein, human MeSH Prohlížeč
• SMARCA4 protein, human MeSH Prohlížeč
• survivin MeSH
• SWI-SNF-B chromatin-remodeling complex MeSH Prohlížeč
• transformující růstový faktor beta2 MeSH
• transkripční faktor spojený s mikroftalmií MeSH
• transkripční faktory MeSH