Unknown,Transcriptomics,Genomics,Proteomics

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Transcription profiling of human Burkittas lymphoma cell line, P493-6 to identify hypoxia responsive genes


ABSTRACT: Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia. We found that HIF-1 also actively suppresses glucose metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in hypoxic HIF-1α-null cells increases ATP levels, attenuates hypoxic ROS generation and rescues these cells from hypoxia-induced apoptosis. These studies reveal a novel hypoxia-induced metabolic switch that shunts glucose metabolites from the mitochondria to glycolysis to maintain ATP production and to prevent toxic ROS production. Experiment Overall Design: We sought to determine by microarray analysis of gene expression the genes responsive to hypoxia using the human B lymphocyte cell line, P493-6. Hypoxia-responsive genes were globally assessed in cells incubated in 0.1% O2 for 29 hours at which the highest HIF-1 levels were obtained

ORGANISM(S): Homo sapiens

SUBMITTER: Chi Dang 

PROVIDER: E-GEOD-4086 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia.

Kim Jung-whan JW   Tchernyshyov Irina I   Semenza Gregg L GL   Dang Chi V CV  

Cell metabolism 20060301 3


Activation of glycolytic genes by HIF-1 is considered critical for metabolic adaptation to hypoxia through increased conversion of glucose to pyruvate and subsequently to lactate. We found that HIF-1 also actively suppresses metabolism through the tricarboxylic acid cycle (TCA) by directly trans-activating the gene encoding pyruvate dehydrogenase kinase 1 (PDK1). PDK1 inactivates the TCA cycle enzyme, pyruvate dehydrogenase (PDH), which converts pyruvate to acetyl-CoA. Forced PDK1 expression in  ...[more]

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