title: Gene expression profiling reveals the profound upregulation of hypoxia-responsive genes in primary human astrocytes.
abstract: Oxygen is vital for the development and survival of mammals. In response to hypoxia, the brain initiates numerous adaptive responses at the organ level as well as at the molecular and cellular levels, including the alteration of gene expression. Astrocytes play critical roles in the proper functioning of the brain; thus the manner in which astrocytes respond to hypoxia is likely important in determining the outcome of brain hypoxia. Here, we used microarray gene expression profiling and data-analysis algorithms to identify and analyze hypoxia-responsive genes in primary human astrocytes. We also compared gene expression patterns in astrocytes with those in human HeLa cells and pulmonary artery endothelial cells (ECs). Remarkably, in astrocytes, five times as many genes were induced as suppressed, whereas in HeLa and pulmonary ECs, as many as or more genes were suppressed than induced. More genes encoding hypoxia-inducible functions, such as glycolytic enzymes and angiogenic growth factors, were strongly induced in astrocytes compared with HeLa cells. Furthermore, gene ontology and computational algorithms revealed that many target genes of the EGF and insulin signaling pathways and the transcriptional regulators Myc, Jun, and p53 were selectively altered by hypoxia in astrocytes. Indeed, Western blot analysis confirmed that two major signal transducers mediating insulin and EGF action, Akt and MEK1/2, were activated by hypoxia in astrocytes. These results provide a global view of the signaling and regulatory network mediating oxygen regulation in human astrocytes.
authors.affiliation: Department of Environmental Health Sciences, Mailman School of Public Health, Columbia University, New York, New York 10032, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Mense
authors.forename: A
authors.initials: A
authors.lastname: Sengupta
authors.forename: M
authors.initials: M
authors.lastname: Zhou
authors.forename: C
authors.initials: C
authors.lastname: Lan
authors.forename: G
authors.initials: G
authors.lastname: Bentsman
authors.forename: D J
authors.initials: DJ
authors.lastname: Volsky
authors.forename: L
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000465:Algorithms; D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D015687:Cell Hypoxia / Q000235:genetics*; D042783:Endothelial Cells / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006019:Glycolysis / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D015854:Up-Regulation
chemical_list: D042501:Angiogenic Proteins; D051793:Hypoxia-Inducible Factor 1; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human