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Chao Zhang, Chunzhang Yang, Michael J Feldman, Herui Wang, Ying Pang, Dominic M Maggio, Dongwang Zhu, Cody L Nesvick, Pauline Dmitriev, Petra Bullova, Prashant Chittiboina, Roscoe O Brady, Karel Pacak, Zhengping Zhuang
Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi...
May 23, 2017: Oncotarget
L Schito, S Rey, M Konopleva
Hypoxia (low O2) is a fundamental microenvironmental determinant of bone marrow (BM) pathophysiology. Recent data from molecular and clinical studies indicate that hematopoiesis and leukemogenesis are dependent upon hypoxia-inducible factors (HIFs), a family of essential transcriptional activators mediating the metazoan hypoxic response. In blood cancers, the synergism between HIF overexpression and stabilization within the hypoxic BM microenvironment promotes disease progression, therapy resistance and relapse...
May 22, 2017: Oncogene
Luana Schito, Sergio Rey
Dissemination of breast cancer cells (BCCs) to distant sites (metastasis) is the ultimate cause of mortality in patients with breast cancer. Hypoxia (low O2) is a microenvironmental hallmark of most solid cancers arising as a mismatch between cellular O2 consumption and supply. Hypoxic selection of BCCs triggers molecular and cellular adaptations dependent upon hypoxia-inducible factors (HIFs), a family of evolutionarily conserved transcriptional activators that coordinate the expression of numerous genes controlling each step of the metastatic process...
May 16, 2017: Biochimica et Biophysica Acta
Raphael R Fagundes, Cormac T Taylor
The intestinal mucosa is exposed to fluctuations in oxygen levels due to constantly changing rates of oxygen demand and supply and its juxtaposition with the anoxic environment of the intestinal lumen. This frequently results in a state of hypoxia in the healthy mucosa even in the physiologic state. Furthermore, pathophysiologic hypoxia (which is more severe and extensive) is associated with chronic inflammatory diseases including inflammatory bowel disease (IBD). The hypoxia-inducible factor (HIF), a ubiquitously expressed regulator of cellular adaptation to hypoxia, is central to both the adaptive and the inflammatory responses of cells of the intestinal mucosa in IBD patients...
April 13, 2017: Journal of Applied Physiology
Colin E Evans, Asis Palazon, Jingwei Sim, Petros A Tyrakis, Alice Prodger, Xiao Lu, Saria Chan, Pär-Ola Bendahl, Mattias Belting, Love Von Euler, Helene Rundqvist, Randall S Johnson, Cristina Branco
Thrombosis can cause localized ischemia and tissue hypoxia, and both of these are linked to cancer metastasis. Vascular micro-occlusion can occur as a result of arrest of circulating tumour cells in small capillaries, giving rise to microthrombotic events that affect flow, creating localized hypoxic regions. To better understand the association between metastasis and thrombotic events, we generated an experimental strategy whereby we modelled the effect of microvascular occlusion in metastatic efficiency by using inert microbeads to obstruct lung microvasculature before, during and after intravenous tumour cell injection...
May 15, 2017: Biology Open
Miguel A S Cavadas, Alex Cheong, Cormac T Taylor
A sufficient supply molecular oxygen is essential for the maintenance of physiologic metabolism and bioenergetic homeostasis for most metazoans. For this reason, mechanisms have evolved for eukaryotic cells to adapt to conditions where oxygen demand exceeds supply (hypoxia). These mechanisms rely on the modification of pre-existing proteins, translational arrest and transcriptional changes. The hypoxia inducible factor (HIF; a master regulator of gene induction in response to hypoxia) is responsible for the majority of induced gene expression in hypoxia...
February 20, 2017: Experimental Cell Research
Anna K Wakeland, Francesca Soncin, Matteo Moretto-Zita, Ching-Wen Chang, Mariko Horii, Don Pizzo, Katharine K Nelson, Louise C Laurent, Mana M Parast
Villous cytotrophoblasts are epithelial stem cells of the early human placenta, able to differentiate either into syncytiotrophoblasts in floating chorionic villi or extravillous trophoblasts (EVTs) at the anchoring villi. The signaling pathways regulating differentiation into these two lineages are incompletely understood. The bulk of placental growth and development in the first trimester occurs under low oxygen tension. One major mechanism by which oxygen regulates cellular function is through the hypoxia-inducible factor (HIF), a transcription factor complex stabilized under low oxygen tension to mediate cellular responses, including cell fate decisions...
April 2017: American Journal of Pathology
K-J Cheng, Y-Y Bao, S-H Zhou
OBJECTIVE: Hypoxia-inducible factor (HIF) is considered an important transcription factor due to its roles in glycolysis, angiogenesis, cell differentiation, apoptosis, and other cellular pathways. It takes the role in various physiological and pathological states, such as solid tumors, vascular injury, and atherosclerotic lesion progression. In recent studies, HIF is found as a master regulator of body inflammation and immunity, not only in hypoxia but also in normoxia. Nasal inflammation has a close relationship with anoxia...
December 2016: European Review for Medical and Pharmacological Sciences
Ting Wang, Jie Meng, Li Li, Guofan Zhang
Hypoxia-inducible factor (HIF), a critical member of the basic-helix-loop-helix (bHLH)-containing Per-Arnt-Sim (PAS) protein family, is a master transcription factor involved in maintaining oxygen homeostasis. In the present study, we isolated and characterized a novel bHLH-PAS family member, CgHIFα-like gene, from the Pacific oyster Crassostrea gigas, and determined its importance during hypoxia stress. The 3020-bp CgHIFα-like cDNA encoded a protein of 888 amino acids. The predicted CgHIFα-like amino acid sequence was conserved in the N-terminal bHLH, PAS, and PAC domains (but not in the C-terminal domain) and was most closely related to the HIF family in the bHLH-PAS protein phylogenic tree...
2016: PloS One
Da-Yuan Chen, Jacqueline-Alba Fabrizio, Sarah E Wilkins, Keyur A Dave, Jeffrey J Gorman, Jonathan M Gleadle, Stephen B Fleming, Daniel J Peet, Andrew A Mercer
Hypoxia-inducible factor (HIF) is a transcriptional activator with a central role in regulating cellular responses to hypoxia. It is also emerging as a major target for viral manipulation of the cellular environment. Under normoxic conditions, HIF is tightly suppressed by the activity of oxygen-dependent prolyl and asparaginyl hydroxylases. The asparaginyl hydroxylase active against HIF, factor inhibiting HIF (FIH), has also been shown to hydroxylate some ankyrin repeat (ANK) proteins. Using bioinformatic analysis, we identified the five ANK proteins of the parapoxvirus orf virus (ORFV) as potential substrates of FIH...
January 1, 2017: Journal of Virology
Andrew J Bryant, Edward W Scott
Pulmonary hypertension complicating idiopathic pulmonary fibrosis, also known as secondary pulmonary hypertension, represents a major source of morbidity and mortality in affected patients. While the study of primary pulmonary arterial hypertension has yielded several therapies, the same is not true for the treatment of pulmonary hypertension secondary to pulmonary fibrosis. Recent studies have indicated an important role of hypoxia-inducible factor (HIF) - a regulatory protein that is vital in adaptation to hypoxic conditions - in the development of secondary pulmonary hypertension...
2016: Receptors & Clinical Investigation
Ngoc Thi Hong Hoang, Tetsuya Kadonosono, Takahiro Kuchimaru, Shinae Kizaka-Kondoh
Pancreatic cancer is one of the most lethal digestive system cancers with a 5-year survival rate of 4-7%. Despite extensive efforts, recent chemotherapeutic regimens have provided only limited benefits to pancreatic cancer patients. Gemcitabine and TS-1, the current standard-of-care chemotherapeutic drugs for treatment of this severe cancer, have a low response rate. Hypoxia is one of the factors contributing to treatment resistance. Specifically, overexpression of hypoxia-inducible factor, a master transcriptional regulator of cell adaption to hypoxia, is strongly correlated with poor prognosis in many human cancers...
August 2016: Cancer Science
Ana Laura De Lella Ezcurra, Agustina Paola Bertolin, Kevin Kim, Maximiliano Javier Katz, Lautaro Gándara, Tvisha Misra, Stefan Luschnig, Norbert Perrimon, Mariana Melani, Pablo Wappner
Cellular and systemic responses to low oxygen levels are principally mediated by Hypoxia Inducible Factors (HIFs), a family of evolutionary conserved heterodimeric transcription factors, whose alpha- and beta-subunits belong to the bHLH-PAS family. In normoxia, HIFα is hydroxylated by specific prolyl-4-hydroxylases, targeting it for proteasomal degradation, while in hypoxia the activity of these hydroxylases decreases due to low oxygen availability, leading to HIFα accumulation and expression of HIF target genes...
May 2016: PLoS Genetics
Yuki Hirota-Takahata, Hideki Kobayashi, Masaaki Kizuka, Takao Ohyama, Michiko Kitamura-Miyazaki, Yasuhiro Suzuki, Mie Fujiwara, Mutsuo Nakajima, Osamu Ando
In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC50 values of 8 and 17 ng ml(-1), respectively. They are highly potent activators of HIF and thus may be therapeutically useful for erythropoiesis and neural cell protection...
October 2016: Journal of Antibiotics
Carsten C Scholz, Javier Rodriguez, Christina Pickel, Stephen Burr, Jacqueline-Alba Fabrizio, Karen A Nolan, Patrick Spielmann, Miguel A S Cavadas, Bianca Crifo, Doug N Halligan, James A Nathan, Daniel J Peet, Roland H Wenger, Alex Von Kriegsheim, Eoin P Cummins, Cormac T Taylor
The asparagine hydroxylase, factor inhibiting HIF (FIH), confers oxygen-dependence upon the hypoxia-inducible factor (HIF), a master regulator of the cellular adaptive response to hypoxia. Studies investigating whether asparagine hydroxylation is a general regulatory oxygen-dependent modification have identified multiple non-HIF targets for FIH. However, the functional consequences of this outside of the HIF pathway remain unclear. Here, we demonstrate that the deubiquitinase ovarian tumor domain containing ubiquitin aldehyde binding protein 1 (OTUB1) is a substrate for hydroxylation by FIH on N22...
January 2016: PLoS Biology
Yogesh Saini, Steven P Proper, Peter Dornbos, Krista K Greenwood, Anna K Kopec, Scott G Lynn, Elizabeth Grier, Lyle D Burgoon, Timothy R Zacharewski, Russell S Thomas, Jack R Harkema, John J LaPres
Hypoxia is a state of decreased oxygen reaching the tissues of the body. During prenatal development, the fetus experiences localized occurrences of hypoxia that are essential for proper organogenesis and survival. The response to decreased oxygen availability is primarily regulated by hypoxia-inducible factors (HIFs), a family of transcription factors that modulate the expression of key genes involved in glycolysis, angiogenesis, and erythropoiesis. HIF-1α and HIF-2α, two key isoforms, are important in embryonic development, and likely are involved in lung morphogenesis...
2015: PloS One
L Wang, S Cui, L Ma, L Kong, X Geng
Oxygen is essential for aerobic life, and hypoxia has very severe consequences. Organisms need to overcome low oxygen levels to maintain biological functions during normal development and in disease states. The mechanism underlying the hypoxic response has been widely investigated in model animals such as Drosophila melanogaster and Caenorhabditis elegans. Hypoxia-inducible factor (HIF), a key gene product in the response to oxygen deprivation, is primarily regulated by prolyl hydroxylase domain enzymes (PHDs)...
December 2015: Insect Molecular Biology
Murtaza M Tambuwala, Mario C Manresa, Eoin P Cummins, Vincenzo Aversa, Ivan S Coulter, Cormac T Taylor
Targeting hypoxia-sensitive pathways has recently been proposed as a new therapeutic approach to the treatment of intestinal inflammation. HIF-hydroxylases are enzymes which confer hypoxic-sensitivity upon the hypoxia-inducible factor (HIF), a major regulator of the adaptive response to hypoxia. Previous studies have shown that systemic (intraperitoneal) administration of hydroxylase inhibitors such as dimethyloxalylglycine (DMOG) is profoundly protective in multiple models of colitis, however the therapeutic potential of this approach is limited due to potential side-effects associated with systemic drug exposure and the fact that orally delivered DMOG is ineffective (likely due to drug inactivation by gastric acid)...
November 10, 2015: Journal of Controlled Release: Official Journal of the Controlled Release Society
Caleb J Kelly, Leon Zheng, Eric L Campbell, Bejan Saeedi, Carsten C Scholz, Amanda J Bayless, Kelly E Wilson, Louise E Glover, Douglas J Kominsky, Aaron Magnuson, Tiffany L Weir, Stefan F Ehrentraut, Christina Pickel, Kristine A Kuhn, Jordi M Lanis, Vu Nguyen, Cormac T Taylor, Sean P Colgan
Interactions between the microbiota and distal gut are fundamental determinants of human health. Such interactions are concentrated at the colonic mucosa and provide energy for the host epithelium through the production of the short-chain fatty acid butyrate. We sought to determine the role of epithelial butyrate metabolism in establishing the austere oxygenation profile of the distal gut. Bacteria-derived butyrate affects epithelial O2 consumption and results in stabilization of hypoxia-inducible factor (HIF), a transcription factor coordinating barrier protection...
May 13, 2015: Cell Host & Microbe
Ellen Marks, Bridie J Goggins, Jocelle Cardona, Siobhan Cole, Kyra Minahan, Sean Mateer, Marjorie M Walker, Robert Shalwitz, Simon Keely
BACKGROUND: Pharmacological induction of hypoxia-inducible factor (HIF), a global transcriptional regulator of the hypoxic response, by prolyl hydroxylase inhibitors (PHDi) is protective in murine models of colitis, and epithelial cells are critical for the observed therapeutic efficacy. Because systemic HIF activation may lead to potentially negative off-target effects, we hypothesized that targeting epithelial HIF through oral delivery of PHDi would be sufficient to protect against colitis in a mouse model...
February 2015: Inflammatory Bowel Diseases
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