Transcriptional responses to hypoxia are primarily mediated by hypoxia-inducible factor (HIF), a heterodimer of HIF-α and the aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1α and HIF-2α subunits are structurally similar in their DNA binding and dimerization domains but differ in their transactivation domains, implying they may have unique target genes. Previous studies using Hif-1α−/− embryonic stem and mouse embryonic fibroblast cells show that loss of HIF-1α eliminates all oxygen-regulated transcriptional responses analyzed, suggesting that HIF-2α is dispensable for hypoxic gene regulation. In contrast, HIF-2α has been shown to regulate some hypoxia-inducible genes in transient transfection assays and during embryonic development in the lung and other tissues. To address this discrepancy, and to identify specific HIF-2α target genes, we used DNA microarray analysis to evaluate hypoxic gene induction in cells expressing HIF-2α but not HIF-1α. In addition, we engineered HEK293 cells to express stabilized forms of HIF-1α or HIF-2α via a tetracycline-regulated promoter. In this first comparative study of HIF-1α and HIF-2α target genes, we demonstrate that HIF-2α does regulate a variety of broadly expressed hypoxia-inducible genes, suggesting that its function is not restricted, as initially thought, to endothelial cell-specific gene expression. Importantly, HIF-1α (and not HIF-2α) stimulates glycolytic gene expression in both types of cells, clearly showing for the first time that HIF-1α and HIF-2α have unique targets.

Differential Roles of Hypoxia-Inducible Factor 1α (HIF-1α) and HIF-2α in Hypoxic Gene Regulation

http://www.rug.nl/research/gastroenterology-and-hepatology/pdf/jhep06.pdf

Superoxide anions and hydrogen peroxide induce hepatocyte death by different mechanisms: Involvement of JNK and ERK MAP kinases

The activation of the nuclear factor-κB (NF-κB) family of transcription factors rapidly induces the upregulation of inflammatory and antiapoptotic genes including the cellular inhibitor of apoptosis 2 (cIAP2; also known as HIAP1 or BIRC3) (25). The ciap2 gene was first identified as a member of the evolutionarily conserved IAP family of proteins (14) that are critical repressors of apoptosis. In addition, cIAP2 is a highly inducible gene that, along with cIAP1, is a component of the tumor necrosis factor receptor 2 (TNFR2) complex and, therefore, is a constituent of the TNF alpha (TNF-α) signaling pathway (19). cIAP2 has been demonstrated to inhibit cell death by directly repressing the proapoptotic activity of a family of cysteine proteases (25), caspases, as well as targeting proapoptotic components of the TNF-α signaling pathway for ubiquitin degradation (17). Despite these findings, the precise antiapoptotic mechanisms, as well as a pathophysiological role for cIAP2 has yet to be determined.

The extent of cytokine response to inflammatory agents, such as lipopolysaccharide (LPS; the biologically active element of the bacterial gram-negative membrane component endotoxin), is regulated by NF-κB. Under normal conditions an inflammatory response is beneficial in controlling invading pathogens and in clearing debris. However, a systemic activation of host macrophages by LPS can induce a hyperinflammatory response resulting in pathogenic endotoxic shock (23). LPS-induced activation of macrophages is typically associated with the production of inflammatory mediator cytokines such as TNF-α and interleukin-1β (IL-1β) (11). These cytokines act synergistically in the initiation of the inflammatory cascade of sepsis (2), resulting in hypotension, tachycardia, systemic edema, disseminated intravascular coagulation, and finally multiple organ system failure.

LPS specifically binds the macrophage cell surface receptor, CD14 (6), which subsequently interacts with the Toll-like receptor 4 (TLR4) (1). TLR4 next recruits the Toll-adaptor protein, myeloid differentiation factor 88 (MyD88) (26), to activate NF-κB and thereby induce the upregulation of proinflammatory cytokines. Activation by LPS of a macrophage results in enhanced phagocytosis of bacteria and the release of cytokines, prompting other macrophages, phagocytes, and T cells to the site of infection. This initiates a proinflammatory response and thereby influences the nature of the adaptive immune response. Macrophages are now well recognized to be the primary mediators for the lethal effects caused by bacterium- or LPS-induced septic shock (10).

LPS activation is known to impart a macrophage with an increased resistance against apoptotic triggers. An inflammatory response produces nitric oxide, reactive oxygen intermediates, and the upregulation of Fas ligand on immune-regulating lymphocytes, all of which are detrimental to both invading pathogens and resident cells. This LPS-induced apoptotic resistance is essential for macrophages to function within an inherently hostile, antimicrobial proinflammatory environment. Considerable interest in the function of cIAP2 has arisen from its role as a major NF-κB-regulated survival factor. cIAP2 has been suggested to be the essential component chiefly responsible for protecting rat hepatocytes from an LPS-induced lethal assault (22).

Given that cIAP2 is a potential key survival factor induced via NF-κB activation in many cells including macrophages, we investigated whether cIAP2 could be an essential component during an innate proinflammatory response. Surprisingly, our studies demonstrate that cIAP2−/− mice display profound resistance to LPS-induced endotoxic shock, specifically via an attenuated inflammatory response. We show that cIAP2−/− macrophage cells are highly susceptible to apoptosis in an LPS-induced proinflammatory environment, indicating that cIAP2 is a critical factor in maintaining a normal innate immune inflammatory response.

Inhibitor of apoptosis protein cIAP2 is essential for lipopolysaccharide-induced macrophage survival.

Inhibitor of apoptosis proteins (IAPs) c-IAP1 and c-IAP2 were identified as part of the tumor necrosis factor receptor 2 (TNFR2) signaling complex and have been implicated as intermediaries in tumor necrosis factor alpha signaling. Like all RING domain-containing IAPs, c-IAP1 and c-IAP2 have ubiquitin protein ligase (E3) activity. To explore the function of c-IAP1 in a physiologic setting, c-IAP1-deficient mice were generated by homologous gene recombination. These animals are viable and have no obvious sensitization to proapoptotic stimuli. Cells from c-IAP1 / mice do, however, express markedly elevated levels of c-IAP2 protein in the absence of increased c-IAP2 mRNA. In contrast to reports implicating c-IAPs in the activation of NF-B, resting and cytokine-induced NF-B activation was not impaired in c-IAP1-deficient cells. Transient transfection studies with wild-type and E3-defective c-IAP1 revealed that c-IAP2 is a direct target for c-IAP1mediated ubiquitination and subsequent degradation, which are potentiated by the adaptor function of TRAF2. Thus, the c-IAPs represent a pair of TNFR-associated ubiquitin protein ligases in which one regulates the expression of the other by a posttranscriptional and E3-dependent mechanism.

Posttranscriptional downregulation of c-IAP2 by the ubiquitin protein ligase c-IAP1 in vivo.

IL-1β and TGFβ2 synergistically induce endothelial to mesenchymal transition in an NFκB-dependent manner

Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappa B-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

BACKGROUND/AIMS
In acute liver failure, hepatocytes are exposed to various cytokines that activate both cell survival and apoptotic pathways. NF-kappaB is a central transcription factor in these responses. Recent studies indicate that blocking NF-kappaB causes apoptosis, indicating the existence of NF-kappaB-regulated anti-apoptotic genes. In the present study the relationship between NF-kappaB activation and apoptosis has been investigated in hepatocytes.


METHODS
Primary rat hepatocytes were exposed to a cytokine mixture of tumor necrosis factor alpha, interleukin-1beta, interferon-gamma and lipopolysaccharide. Modulation of signalling pathways was performed by using dominant negative adenoviral constructs. Apoptosis and NF-kappaB activation were determined by caspase-3 activity, Hoechst staining and electrophoretic mobility shift assay, respectively. Furthermore, expression and regulation of apoptosis-related genes were investigated.


RESULTS
(1) Inhibition of NF-kappaB activation results in apoptosis. (2) Inhibitor of apoptosis protein (IAP) family members, inhibitor of apoptosis protein1 (cIAP1), and X-chromosome-linked IAP, are expressed in rat hepatocytes. cIAP2 is induced by cytokines in an NF-kappaB-dependent manner and overexpression of cIAP2 inhibits apoptosis. (3) The anti-apoptotic Bcl-2 family member A1/Bfl-1 and the pro-apoptotic members Bak and Bid are induced by cytokines and NF-kappaB-dependent. (4) Nitric oxide inhibits caspase-3 activity in hepatocytes.


CONCLUSIONS
In inflammatory conditions, hepatocyte survival is dependent on NF-kappaB activation and cIAP2 contributes significantly to this protection.

Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

P Liston

Author Tools

Chat about Author

Papers

Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes: NF-kappa B-regulated inhibitor of apoptosis protein 2 (cIAP2) prevents apoptosis

Cytokine regulation of pro- and anti-apoptotic genes in rat hepatocytes