669 publications from this institution
Reflecting an increasing emphasis on collaborative science, the number of authors on published articles has markedly risen with time. With this trend, we see an increase in papers designating 2 or more co-first authors. To improve transparency in how such designations are made and reduce bias in the assignment of order, the JCI is now requiring an explanation for how the first-author position is determined when shared among contributing authors.
Abstract In Chapters 5 through 14, mutations that affect the structure and/or function of specific transcription factors and result in human disease will be described. As in the previous chapter, the intent is not to catalogue all known mutations but rather to provide examples that illustrate principles of molecular pathophysiology that will be applicable to the ever expanding list of such conditions that is being reported in the molecular biology and clinical literature. In contrast to the mutations in cis-acting elements, the mutations in trans-acting factors affect the structure of the protein product of a gene. In the text, gene symbols will be indicated by italicized letters (all capitalized for human genes, first letter only for mouse genes), whereas the protein product of a gene will be indicated by unitalicized capital letters (for both human and mouse proteins). Missense mutations result in substitution of one amino acid for another and will be designated in the text using the single-letter code for amino acids (see Table 5.1). For example, the mutation C23S (due to a TGT AGT transversion) would result in substitution of serine for cysteine at residue 23 of the protein. Nonsense mutations result in premature termination of translation, which is designated by an X. Thus, the mutation C23X (due to a TGT TGA transversion) would result in translation of a truncated polypeptide containing only 22 amino acid residues.
Abstract Metazoan life is dependent upon the utilization of O 2 for essential metabolic processes and oxygen homeostasis is an organizing principle for understanding metazoan evolution, ontology, physiology, and pathology. Hypoxia‐inducible factor 1 (HIF‐1) is a transcription factor that is expressed by all metazoan species and functions as a master regulator of oxygen homeostasis. Recent studies have elucidated complex mechanisms by which HIF‐1 activity is regulated and by which HIF‐1 regulates gene expression, with profound consequences for prenatal development, postnatal physiology, and disease pathogenesis. Copyright © 2009 John Wiley & Sons, Inc. This article is categorized under: Physiology > Organismal Responses to Environment
The small subpopulation of breast cancer cells that possess the capability for self-renewal and formation of secondary tumours that recapitulate the heterogeneity of the primary tumour are referred to as tumour-initiating cells or BCSCs (breast cancer stem cells). The hypoxic tumour microenvironment and chemotherapy actively induce the BCSC phenotype. HIFs (hypoxia-inducible factors) are required and molecular mechanisms by which they promote the BCSC phenotype have recently been delineated. HIF inhibitors block chemotherapy-induced enrichment of BCSCs, suggesting that their use may improve the response to chemotherapy and increase the survival of breast cancer patients.
Abstract Hypoxia‐inducible factors mediate adaptive responses to reduced O 2 availability. In patients with obstructive sleep apnoea, repeated episodes of hypoxaemia and reoxygenation (intermittent hypoxia) are sensed by the carotid body (CB). The ensuing CB chemosensory reflex activates the sympathetic nervous system and increased secretion of catecholamines by the adrenal medulla, resulting in hypertension and breathing abnormalities. In the CB, intermittent hypoxia induces the formation of reactive oxygen species (ROS) and increased intracellular Ca 2+ levels, which drive increased expression of hypoxia‐inducible factor (HIF) 1α and a decrease in the levels of HIF‐2α. Intermittent hypoxia increases HIF‐1α‐dependent expression of Nox2 , encoding the pro‐oxidant enzyme NADPH oxidase 2, and decreased HIF‐2α‐dependent expression of Sod2 , encoding the anti‐oxidant enzyme superoxide dismutase 2. These changes in gene expression drive persistently elevated ROS levels in the CB, brainstem, and adrenal medulla that are required for the development of hypertension and breathing abnormalities. The ROS generated by dysregulated HIF activity in the CB results in oxidation and inhibition of haem oxygenase 2, and the resulting reduction in the levels of carbon monoxide leads to increased hydrogen sulfide production, triggering glomus cell depolarization. Thus, the pathophysiology of obstructive sleep apnoea involves the dysregulation of O 2 ‐regulated transcription factors, gasotransmitters, and sympathetic outflow that affects blood pressure and breathing. image
Transcription of the human erythropoietin (EPO) gene is activated in Hep3B cells exposed to hypoxia. Hypoxia-inducible factor 1 (HIF-1) is a nuclear factor whose DNA binding activity is induced by hypoxia in Hep3B cells, and HIF-1 binds at a site in the EPO gene enhancer that is required for hypoxic activation of transcription. In this paper, we demonstrate that HIF-1 DNA binding activity is also induced by hypoxia in a variety of mammalian cell lines in which the EPO gene is not transcribed. The composition of the HIF-1 DNA binding complex and its isolated DNA binding subunit and the mechanism of HIF-1 activation appear to be similar or identical in EPO-producing and non-EPO-producing cells. Transcription of reporter genes containing the EPO gene enhancer is induced by hypoxia in non-EPO-producing cells and mutations that eliminate HIF-1 binding eliminate inducibility. These results provide evidence that HIF-1 and its recognition sequence are common components of a general mammalian cellular response to hypoxia.
