Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hypoxia-inducible factor, a heterodimeric transcription complex, regulates cellular and systemic responses to low oxygen levels (hypoxia) during normal mammalian development or tumor progression. Here, we present evidence that a similar complex mediates response to hypoxia in Caenorhabditis elegans. This complex consists of HIF-1 and AHA-1, which are encoded by C. elegans homologs of the hypoxia-inducible factor (HIF) alpha and beta subunits, respectively. hif-1 mutants exhibit no severe defects under standard laboratory conditions, but they are unable to adapt to hypoxia. Although wild-type animals can survive and reproduce in 1% oxygen, the majority of hif-1-defective animals die in these conditions. We show that the expression of an HIF-1:green fluorescent protein fusion protein is induced by hypoxia and is subsequently reduced upon reoxygenation. Both hif-1 and aha-1 are expressed in most cell types, and the gene products can be coimmunoprecipitated. We conclude that the mechanisms of hypoxia signaling are likely conserved among metazoans. Additionally, we find that nuclear localization of AHA-1 is disrupted in an hif-1 mutant. This finding suggests that heterodimerization may be a prerequisite for efficient nuclear translocation of AHA-1.
 ...
PMID:The Caenorhabditis elegans hif-1 gene encodes a bHLH-PAS protein that is required for adaptation to hypoxia. 1142 34

Hypoxia, a common consequence of solid tumor growth in breast cancer and other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and alterations in microenvironmental pH. Hypoxia-inducible factors, heterodimeric DNA binding complexes composed of two subunits, provide critical regulation of this response. This review presents a synopsis of the genes induced by hypoxia in the context of breast cancer and discusses how upregulation of HIF-1 activity, and the homologous factor HIF-2, are not only fundamental for the adaptation to hypoxia but also may be critical for tumor progression.
 ...
PMID:Hypoxia-induced pathways in breast cancer. 1224 95

HIF-1 is reported to transactivate expression of VEGF, which is an important angiogenic factor. To determine whether HIF-1alpha plays a role in angiogenesis through its regulation of VEGF, we examined expression of HIF-1alpha and its relation to clinicopathologic features, VEGF expression and prognosis of patients with colorectal carcinoma. Expression of HIF-1alpha and VEGF was examined in 4 colorectal carcinoma cell lines (COLO320DM, COLO201, DLD-1, WiDr) and 149 colorectal carcinoma tissues (10 fresh specimens, 139 archival, paraffin-embedded specimens). HIF-1alpha protein levels were increased by hypoxia in 3 of 4 colorectal carcinoma cell lines (COLO201, DLD-1, WiDr), and VEGF mRNA levels were also increased by hypoxia in the same cell lines. In 8 of 10 patients with colorectal cancer, expression of HIF-1alpha and VEGF was increased in tumor tissues compared to corresponding normal mucosa. Of 139 archival specimens of colorectal carcinoma, 81 (58.3%) expressed HIF-1alpha protein at a high level. HIF-1alpha expression was correlated with tumor invasion, tumor stage, lymphatic invasion, venous invasion and liver metastasis. Moreover, HIF-1alpha expression was correlated significantly with VEGF expression and microvessel density. Although there was a tendency for poorer prognosis in patients with high HIF-1alpha-expressing tumors, this correlation was not statistically significant. These findings suggest that HIF-1alpha may play a role in angiogenesis and tumor progression via regulation of VEGF in human colorectal carcinoma.
 ...
PMID:Expression of hypoxia-inducible factor-1alpha is associated with tumor vascularization in human colorectal carcinoma. 1267 75

The hypoxia-inducible factors 1alpha (HIF-1alpha) and 2alpha (HIF-2alpha) 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-1alpha and -2alpha by hypoxia in immortalized mouse embryo fibroblasts (MEFs). We show that oxygen-dependent protein degradation is restricted to HIF-1alpha, as HIF-2alpha protein is detected in MEFs regardless of oxygenation and is localized primarily to the cytoplasm. Endogenous HIF-2alpha remained transcriptionally inactive under hypoxic conditions; however, ectopically overexpressed HIF-2alpha 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-1alpha but has no effect on HIF-2alpha-mediated transcription in MEFs. We propose that HIF-2alpha is not a redundant transcription factor of HIF-1alpha for hypoxia-induced gene expression and show evidence that there is a cell type-specific modulator(s) that enables selective activation of HIF-1alpha but not HIF-2alpha in response to low-oxygen stress.
 ...
PMID:Hypoxia-induced gene expression occurs solely through the action of hypoxia-inducible factor 1alpha (HIF-1alpha): role of cytoplasmic trapping of HIF-2alpha. 1283 81

Hypoxic stress is one of the major selective pressures in the microenvironment of solid tumors, and overcoming this restriction is essential for tumor progression. One of the key factors driving the cellular response to lack of oxygen is hypoxia inducible factor (HIF), a key transcriptional factor. The level of the alpha subunit of HIF-1 is regulated by rapid degradation that is controlled by a family of prolyl hydroxylases (PHDs/EGLNs), the activity of which depends on oxygen availability. Our study shows that ectopic expression of mPHD1 suppressed accumulation of HIF-1alpha and secretion of Vascular Endothelial Growth Factor after treatment of cells with a hypoxia-mimetic drug. Furthermore, when colon carcinoma cells expressing mPHD1 were injected into nude mice, tumor growth was inhibited, and the inhibition of tumor growth was correlated with increased necrosis and a striking decrease in microvessel density. These data demonstrate that inhibition of hypoxia-induced activation of HIF-1alpha through activation of HIF-hydroxylase can provide a novel therapeutic strategy for inhibition of tumor growth and neovascularization and support the development of gene transfer approaches based on the activation of HIF-prolyl hydroxylases.
 ...
PMID:Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. 1469 94

HIF-1 is a key factor in cancer progression. Efforts are underway to identify and develop small molecules that inhibit HIF-1 transcriptional activity. What are the best targets and the best ways to develop HIF-1 inhibitors are open questions. However, several "nonselective" HIF-1 inhibitors have been identified, which are either in the clinic or under development. In this article, we discuss how topoisomerase I poisons, which inhibit HIF-1a protein accumulation and transcriptional activity, can be "rationally" used to target HIF-1 for cancer therapy.
 ...
PMID:Targeting topoisomerase I to inhibit hypoxia inducible factor 1. 1471 84

Hypoxia-inducible factor-1alpha (HIF-1alpha) plays a central role in oxygen homeostasis by inducing the expression of a broad range of genes in a hypoxia-dependent manner. Here, we show that the orphan nuclear receptor Nur77 is an important regulator of HIF-1alpha. Under hypoxic conditions, Nur77 protein and transcripts were induced in a time-dependent manner. When Nur77 was exogenously introduced, it enhanced the transcriptional activity of HIF-1, whereas the dominant negative Nur77 mutant abolished the function of HIF-1. The HIF-1alpha protein was greatly increased and completely localized in the nucleus when coexpressed with Nur77. The N-terminal transactivation domain of Nur77 was required and sufficient for the activation of HIF-1alpha. The association of HIF-1alpha with von Hippel-Lindau protein was not affected, whereas that with mouse double minute 2 (MDM2) was greatly reduced in the presence of Nur77. Further we found that the expression of MDM2 was repressed at transcription level in the presence of Nur77 as well as under hypoxic conditions. Finally, PD98059 decreased Nur77-induced HIF-1alpha stability and recovered MDM2 expression, indicating that the extracellular signal-regulated kinase pathway is critical in the Nur77-induced activation of HIF-1alpha. Together, our results demonstrate a novel function for Nur77 in the stabilization of HIF-1alpha and suggest a potential role for Nur77 in tumor progression and metastasis.
 ...
PMID:Novel function of orphan nuclear receptor Nur77 in stabilizing hypoxia-inducible factor-1alpha. 1538 70

Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1alpha versus HIF-2alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.
 ...
PMID:Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. 1677 2

Macrophage migration inhibitory factor (MIF) is a well-described pro-inflammatory mediator that has also been implicated in the process of oncogenic transformation and tumor progression. However, despite the compelling evidence that MIF is overexpressed in, and contributes to, the pathology of inflammatory and malignant diseases the mechanisms that contribute to exaggerated expression of MIF have been poorly described. Here we show that hypoxia, and specifically HIF-1alpha, is a potent and rapid inducer of MIF expression. In addition, we demonstrate that hypoxia-induced MIF expression is dependent upon a HRE in the 5'UTR of the MIF gene but is further modulated by CREB expression. We propose a model where hypoxia-induced MIF expression is driven by HIF-1 but amplified by hypoxia-induced degradation of CREB. Given the importance of MIF in inflammatory and malignant diseases these data reveal a HIF-1-mediated pathway as a potential therapeutic target for suppression of MIF expression in hypoxic tissues.
 ...
PMID:Dual regulation of macrophage migration inhibitory factor (MIF) expression in hypoxia by CREB and HIF-1. 1685 77

Hypoxia is a dynamic feature of the tumor microenvironment that contributes to cancer progression. In order to adapt and overcome hypoxic stress, tumor cells activate survival pathways that attempt to couple metabolic processes to reduced energy availability due to oxygen deprivation. While the hypoxia-inducible factors HIF-1 and HIF-2 are critical to the cellular response to hypoxia, HIF-independent processes are known to contribute to this adaptation. Recent evidence demonstrates that hypoxia activates components of the Unfolded Protein Response (UPR), a coordinated program that regulates cellular adaptation to increased levels of unfolded proteins in the endoplasmic reticulum (ER). Here we review the evidence implicating the ER kinase PERK, its downstream target translation initiation factor eIF2alpha, and the subsequent translational upregulation of the transcription factor ATF4 in this response. Not only are cells with compromised PERK-eIF2alpha-ATF4 signaling more sensitive to hypoxic stress in vitro but they also form tumors that grow slower in vivo with smaller hypoxic areas, indicating that the PERK-eIF2alpha-ATF4 pathway confers a survival advantage for tumor cells under hypoxia. These results, together with evidence for an involvement of other UPR pathways and ER stress proteins in hypoxia tolerance and tumor maintenance, point to a central role for UPR activation in tumor progression and suggest that this response may offer an attractive target for new anti-tumor modalities.
 ...
PMID:The PERK/eIF2alpha/ATF4 module of the UPR in hypoxia resistance and tumor growth. 1686 99


1 2 3 4 5 6 7 8 9 10 Next >>