The Krüppel-like zinc finger transcription factor, GLI-similar 1, is regulated by hypoxia-inducible factors via non-canonical mechanisms (original) (raw)
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Cell Stem Cell, 2014
Pluripotent stem cells have distinct metabolic requirements, and reprogramming cells to pluripotency requires a shift from oxidative to glycolytic metabolism. Here, we show that this shift occurs early during reprogramming of human cells and requires hypoxia-inducible factors (HIFs) in a stagespecific manner. HIF1a and HIF2a are both necessary to initiate this metabolic switch and for the acquisition of pluripotency, and the stabilization of either protein during early phases of reprogramming is sufficient to induce the switch to glycolytic metabolism. In contrast, stabilization of HIF2a during later stages represses reprogramming, partly because of the upregulation of TNF-related apoptosis-inducing ligand (TRAIL). TRAIL inhibits induced pluripotent stem cell (iPSC) generation by repressing apoptotic caspase 3 activity specifically in cells undergoing reprogramming but not human embryonic stem cells (hESCs), and inhibiting TRAIL activity enhances human iPSC generation. These results shed light on the mechanisms underlying the metabolic shifts associated with the acquisition of a pluripotent identity during reprogramming. Cell Stem Cell HIF1 and HIF2 in Reprogramming
The Kaohsiung journal of medical sciences, 2015
Eukaryotic organisms require oxygen homeostasis to maintain proper cellular function for survival. During conditions of low oxygen tension (hypoxia), cells activate the transcription of genes that induce an adaptive response, which supplies oxygen to tissues. Hypoxia and hypoxia-inducible factors (HIFs) may contribute to the maintenance of putative cancer stem cells, which can continue self-renewal indefinitely and express stemness genes in hypoxic stress environments (stem cell niches). Reactive oxygen species (ROS) have long been recognized as toxic by-products of aerobic metabolism that are harmful to living cells, leading to DNA damage, senescence, or cell death. HIFs may promote a cancer stem cell state, whereas the loss of HIFs induces the production of cellular ROS and activation of proteins p53 and p16(Ink4a), which lead to tumor cell death and senescence. ROS seem to inhibit HIF regulation in cancer cells. By contrast, controversial data have suggested that hypoxia increase...
Hypoxia-Inducible Transcription Factors and Their Role in Renal Disease
Seminars in Nephrology, 2007
The 2 hypoxia inducible factors (HIF)-1␣ and HIF-2␣ are key mediators of cellular adaptation to hypoxia. They show a specific distribution pattern and possibly have complementary transcriptional targets in the kidney: HIF-1␣ is found mainly in tubular and HIF-2␣ in peritubular interstitial, endothelial, and glomerular cells. Both isoforms are regulated by oxygen-dependent hydroxylation of specific amino acid residues, which determines protein stability and transcriptional activity. Small molecule inhibitors of HIF hydroxylases act as pharmacologic inducers of HIF. HIF target genes are involved in cellular mechanisms that increase hypoxia tolerance or improve oxygen supply at the systemic or regional level, but also have been implicated in cellular apoptosis and profibrotic mechanisms. In experimental acute kidney injury the up-regulation of HIF either through endogenous hypoxiasensing or after pharmacologic HIF stabilization confers tissue protection. Thus, HIF stabilization offers a promising novel and clinically feasible approach for nephroprotection. On the other hand, continuous activation of the HIF system occurs in kidney cancer and potentially promotes tumor growth. HIF therefore also is explored as a target for anticancer therapy.
Cancer research, 2005
Cells exposed to hypoxia respond by increasing the level of hypoxia-inducible factor-1 (HIF-1). This factor then activates a number of genes by binding to hypoxia response elements in their promoter regions. A second hypoxia-responsive factor, HIF-2, can activate many of the same genes as HIF-1. Overexpression of HIFs accompanies the pathogenesis of many tumors. It is unclear, however, as to the respective role of these factors in responsiveness to hypoxia and other stresses. To address this issue, we used microarray technology to study the genes activated in HEK293T cells by hypoxia or transfection with the alpha chain of HIF-1 (or mutant HIF-1 resistant to degradation) or HIF-2. Fifty-six genes were found to be up-regulated at least 3-fold by either hypoxia or transfection. Of these, 21 were elevated both by transfection with HIF-1alpha and with HIF-2alpha, and 14 were preferentially activated by HIF-1alpha including several involved in glycolysis. Ten genes were preferentially ac...
PLOS Medicine, 2006
We analyzed the temporal changes in global transcript levels in response to hypoxia in primary renal proximal tubule epithelial cells, breast epithelial cells, smooth muscle cells, and endothelial cells with DNA microarrays. The extent of the transcriptional response to hypoxia was greatest in the renal tubule cells. This heightened response was associated with a uniquely high level of HIF-1a RNA in renal cells, and it could be diminished by reducing HIF-1a expression via RNA interference. A gene-expression signature of the hypoxia response, derived from our studies of cultured mammary and renal tubular epithelial cells, showed coordinated variation in several human cancers, and was a strong predictor of clinical outcomes in breast and ovarian cancers. In an analysis of a large, published gene-expression dataset from breast cancers, we found that the prognostic information in the hypoxia signature was virtually independent of that provided by the previously reported wound signature and more predictive of outcomes than any of the clinical parameters in current use.
Molecular and Cellular Biology, 2003
The hypoxia-inducible factors 1␣ (HIF-1␣) and 2␣ (HIF-2␣) have extensive structural homology and have been identified as key transcription factors responsible for gene expression in response to hypoxia. They play critical roles not only in normal development, but also in tumor progression. Here we report on the differential regulation of protein expression and transcriptional activity of HIF-1␣ and -2␣ by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1␣, as HIF-2␣ protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2␣ remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2␣ translocated into the nucleus and could stimulate expression of hypoxia-inducible genes. We show that the factor inhibiting HIF-1 can selectively inhibit the transcriptional activity of HIF-1␣ but has no effect on HIF-2␣-mediated transcription in MEFs. We propose that HIF-2␣ is not a redundant transcription factor of HIF-1␣ for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1␣ but not HIF-2␣ in response to low-oxygen stress.
Scientific Reports
Human embryonic and induced pluripotent stem cells are self-renewing pluripotent stem cells (hPSCs) that can differentiate into a wide range of specialized cells. Although moderate hypoxia (5% O2) improves hPSC self-renewal, pluripotency, and cell survival, the effect of acute severe hypoxia (1% O2) on hPSC viability is still not fully elucidated. In this sense, we explore the consequences of acute hypoxia on hPSC survival by culturing them under acute (maximum of 24 h) physical severe hypoxia (1% O2). After 24 h of hypoxia, we observed HIF-1α stabilization concomitant with a decrease in cell viability. We also observed an increase in the apoptotic rate (western blot analysis revealed activation of CASPASE-9, CASPASE-3, and PARP cleavage after hypoxia induction). Besides, siRNA-mediated downregulation of HIF-1α and P53 did not significantly alter hPSC apoptosis induced by hypoxia. Finally, the analysis of BCL-2 family protein expression levels disclosed a shift in the balance betwee...