A5071613563- Cancer, Hypoxia, and Metabolism
- High Altitude and Hypoxia
- Mitochondrial Function and Pathology
- Liver Disease and Transplantation
- Adipose Tissue and Metabolism
- Nitric Oxide and Endothelin Effects
- Metalloenzymes and iron-sulfur proteins
- Cardiovascular, Neuropeptides, and Oxidative Stress Research
- Cancer-related gene regulation
- Biochemical effects in animals
- Advanced Proteomics Techniques and Applications
- Heme Oxygenase-1 and Carbon Monoxide
- Hydrogen Storage and Materials
- Eicosanoids and Hypertension Pharmacology
- Fungal and yeast genetics research
- RNA modifications and cancer
- Liver Disease Diagnosis and Treatment
- Cancer Genomics and Diagnostics
- Hybrid Renewable Energy Systems
- Electrocatalysts for Energy Conversion
- Trace Elements in Health
- Cardiomyopathy and Myosin Studies
- Hemoglobin structure and function
- melanin and skin pigmentation
- Iron Metabolism and Disorders
University of Pennsylvania
2011-2023
University of Alabama at Birmingham
2004
University of Calgary
1999-2002
Canadian Society of Intestinal Research
2001
State University of New York
1991
Stony Brook University
1991
Protein-protein interactions resulting in dimerization and heterodimerization are of central importance the control gene expression cell function. Proteins that share 52-residue LIM/double zinc-finger domain involved a wide range developmental cellular controls. Some these functions have been hypothesized to involve protein dimerization. In present report we demonstrate, using both vitro cell-based studies, representative LIM protein, human cysteine-rich (hCRP), can efficiently homodimerize....
Haploid a and alpha cells of yeast respond to the pheromones alpha- a-factor, respectively, by increasing transcription many genes whose products are essential for mating. The STE12 protein acts in this process binding DNA sequence that mediates increased pheromone-responsive genes. We show here hybrid containing fused DNA-binding domain GAL4 can activate reporter gene GAL4-binding sites but only after treatment with pheromone. Thus, alone, when bound DNA, is sufficient mediate...
Endothelin-1 (ET-1) stimulation of endothelial nitric oxide synthase (eNOS) via pulmonary endothelin B (ET ) receptors and intravascular macrophage accumulation with expression inducible (iNOS) heme oxygenase-1 (HO-1) are implicated in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). Our aim was to evaluate the role ET-1 development HPS. The time course molecular physiological changes HPS effects selective receptor antagonists vivo were assessed CBDL....
The enzyme heme oxygenase (HO), which exists in inducible (HO-1) and constitutive (HO-2) isoforms, degrades to biliverdin CO. CO depresses cardiac contraction via cGMP. We aimed clarify a possible role for the HO-CO pathway pathogenesis of cirrhotic cardiomyopathy bile duct-ligated rats. Four weeks after duct ligation or sham operation, rat ventricles were examined HO-1 HO-2 mRNA by RT-PCR protein expression Western blotting. Total HO activity cGMP levels also measured. effects inhibitor,...
Prolyl hydroxylase domain protein 2 (PHD2, also known as Egg Laying Defective Nine homolog 1) is a key oxygen-sensing in metazoans. In an oxygen-dependent manner, PHD2 site-specifically prolyl hydroxylates the master transcription factor of hypoxic response, hypoxia-inducible factor-α (HIF-α), thereby targeting HIF-α for degradation. this report we show that heat shock 90 (HSP90) co-chaperones p23 and FKBP38 interact via conserved Pro-Xaa-Leu-Glu motif (where Xaa = any amino acid) these...
The biogenesis of cytosolic iron-sulfur (Fe-S) proteins in mammalian cells is poorly understood. In Saccharomyces cerevisiae, there a pathway dedicated to Fe-S protein maturation that involves several essential proteins. One these Nar1, which intriguingly homologous iron-only hydrogenases, ancient enzymes catalyze the formation hydrogen gas anaerobic bacteria. There are two orthologues Nar1 cells, hydrogenase-like 1 (IOP1) and IOP2 (also known as nuclear prelamin A recognition factor). We...
Tibetans have adapted to the chronic hypoxia of high altitude and display a distinctive suite physiologic adaptations, including augmented hypoxic ventilatory response resistance pulmonary hypertension. Genome-wide studies consistently identified compelling genetic signatures natural selection in two genes Hypoxia Inducible Factor pathway, PHD2 HIF2A The product former induces degradation latter. Key issues regarding Tibetan are whether it is gain-of-function or loss-of-function allele, how...
Iron-sulfur proteins play an essential role in a variety of biologic processes and exist multiple cellular compartments. The biogenesis these has been the subject extensive investigation, particular focus placed on pathways that assemble iron-sulfur clusters different Iron-only hydrogenase-like protein 1 (IOP1; also known as nuclear prelamin A recognition factor like protein, or NARFL) is human homologous to Nar1, Saccharomyces cerevisiae that, turn, component cytosolic assembly pathway...
Portal hypertension is associated with hyperdynamic circulation, but the pathogenesis remains unclear. To clarify role of central cardiovascular regulatory mechanisms, several protocols were conducted in rats portal due to vein stenosis (PVS). Neuronal activation was quantified by immunohistochemical staining for Fos, protein product c-fos gene. Fos expression brain nuclei cardiovascular-regulatory roles examined at 1, 3, 5, and 10 days following PVS surgery. This correlated development...
A central means by which mammalian cells respond to low oxygen tension is through the activation of transcription factor HIF-1 (hypoxia-inducible factor-1). Under normoxic conditions, HIF-1α (the α subunit HIF-1) targeted for rapid degradation ubiquitin–proteasome pathway. hypoxic this inhibited, thereby leading stabilization and HIF-1α. Here, we report identification IOP1 (iron-only hydrogenase-like protein 1), a homologous with enzymes present in anaerobic organisms that contain...
For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies provided evidence for positive selection acting in on HIF2A (also known as EPAS1) locus, which encodes a central transcription factor hypoxia-inducible pathway. However, precise mechanism by this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes,...
Prolyl hydroxylation is a PTM that plays an important role in the formation of collagen fibrils and oxygen-dependent regulation hypoxia inducible factor-α (HIF-α). While this modification has been well characterized context these proteins, it remains unclear to what extent occurs remaining mammalian proteome. We explored question using MS analyze cellular extracts subjected various fractionation strategies. In one strategy, we employed von Hippel Lindau tumor suppressor protein, which...
Prolyl hydroxylase domain protein 2 (PHD2) (also known as EGLN1) is a key oxygen sensor in mammals that posttranslationally modifies hypoxia-inducible factor α (HIF-α) and targets it for degradation. In addition to its catalytic domain, PHD2 contains an evolutionarily conserved zinc finger which we have previously proposed recruits the HSP90 pathway promote HIF-α hydroxylation. Here, provide evidence this recruitment critical both vitro vivo We show vitro, can function autonomous facilitate...
Portal hypertension due to either prehepatic portal or cirrhosis is associated with cardiovascular derangement. We aimed delineate regulatory mechanisms in the brain stem nuclei rat models of and cirrhosis. Neuronal activation nucleus solitary tract (NTS) ventrolateral medulla (VLM) were assessed by immunohistochemical staining for immediate-early gene product Fos. In same sections, catecholaminergic neurons counted tyrosine hydroxylase (TH) staining. Ninety minutes after hypotensive...
Prolyl hydroxylase domain protein 2 (PHD2) is a well-known master oxygen sensor. However, the role of PHD2 in tumor initiation remains controversial. We find that during transition human nevi to melanoma, expression significantly decreased and lower melanoma associated with worse clinical outcome. Knockdown leads elevated Akt phosphorylation melanocytes. Mice conditional melanocyte-specific Phd2lox/lox (Tyr::CreER;Phd2lox/lox) fail develop pigmented lesions. deletion Phd2 combination...
Numerous mammalian species have adapted to the chronic hypoxia of high altitude. Recent genomic studies identified evidence for natural selection genes and associated genetic changes in these species. A major gap our knowledge is an understanding functional significance, if any, changes. Deer mice (Peromyscus maniculatus) live at both low altitudes North America, providing opportunity identify functionally important High-altitude deer show on Epas1 gene, which encodes hypoxia-inducible...
The prolyl hydroxylase domain (PHD) protein:hypoxia inducible factor (HIF) pathway is the main by which changes in oxygen concentration are transduced to gene expression. In mammals, there three PHD paralogues, and PHD2 has emerged as a particularly critical one for regulating HIF target genes such erythropoietin (EPO), controls red cell mass hematocrit. distinctive among PHDs that it contains an N-terminal MYND-type zinc finger. We have proposed this finger binds Pro-Xaa-Leu-Glu (PXLE)...
Loss of function mutations in the EGLN1 gene are a cause erythrocytosis. encodes for prolyl hydroxylase domain protein 2 (PHD2). PHD2 hydroxylates and downregulates hypoxia-inducible factor-2α (HIF-2α), transcription factor that regulates erythropoiesis. While large majority erythrocytosis-associated occur within its catalytic domain, rare reside zinc finger. This finger binds Pro-Xaa-Leu-Glu motif p23, an HSP90 cochaperone facilitates hydroxylation HIF-α, client. Essentially nothing is...