Hypoxia causes the activation of NF-kappa B and the phosphorylation of I kappa B alpha of both tyrosine and serine residues (Meeting abstract).

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Hypoxia causes the activation of NF-kappa B and the phosphorylation of I kappa B alpha of both tyrosine and serine residues (Meeting abstract).

Proc Annu Meet Am Assoc Cancer Res; 35:A3808 1994. Unique Identifier : AIDSLINE ICDB/95605493
Koong AC; Chen EY; Giaccia AJ; Dept. of Radiation Oncology, Stanford University School of; Medicine, Stanford, CA 94305-5468

Abstract: Transcriptional regulation of gene expression by NF-kappa B is accomplished by translocation of NF-kappa B from the cytoplasm to the nucleus where it is able to bind DNA. The signals for NF-kappa B activation are diverse, but can be classified as protein kinase C (PKC) dependent (eg, oxidative stress) or PKC independent (eg, TNF). We reasoned that NF-kappa B was activated by hypoxia because previous data demonstrated an induction of HIV-1 replication by lowering O2 tensions. To determine whether NF-kappa B could be activated by hypoxia to bind DNA and promote transcription of the HIV promotor, we used immunoblot analysis to show an oxygen dependent dissociation of the inhibitory subunit I kappa B alpha from NF-kappa B, and an oxygen dependent increase in p65 nuclear translocation. This increase in nuclear translocation of p65 resulted in increased DNA binding and an oxygen dependent transactivation of a reporter gene construct containing the HIV promotor ligated to the bacterial chloramphenicol acetyl transferase (CAT) gene. Induction of HIV-CAT seemed to be mediated through NF-kappa B as hypoxia did not induce transcription of the HIV-CAT constructs in which the NF-kappa B binding sites were mutated. To demonstrate a direct link between changes in I kappa B alpha phosphorylation with NF-kappa B activation, we immunoprecipitated I kappa B alpha after varying times of hypoxic exposure and found that both its tyrosine and serine phosphorylation status increased while its threonine phosphorylation status remained unchanged. Furthermore, inhibiting either of these phosphorylation steps was enough to prevent I kappa B alpha dissociation from NF-kappa B and transactivation of the HIV-CAT reporter construct. These results suggest that in vivo, phosphorylation at both tyrosine and serine residues on I kappa B alpha are important regulatory steps in the activation of NF-kappa B.

Keywords: Binding Sites Blotting, Western Cell Hypoxia DNA/METABOLISM NF-kappa B/ANTAGONISTS & INHIB/*METABOLISM Oxygen/METABOLISM Phosphorylation Precipitin Tests Serine/*METABOLISM Trans-Activation (Genetics) Tyrosine/*METABOLISM ABSTRACT
950330
M9530826

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