GENES: STRUCTURE AND REGULATION
Involvement of Two NF-κB Binding Elements in Tumor Necrosis Factor α-, CD40-, and Epstein-Barr Virus Latent Membrane Protein 1-mediated Induction of the Cellular Inhibitor of Apoptosis Protein 2 Gene*

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The antiapoptotic function of NF-κB is believed to be mediated through the induction of antiapoptotic genes. Among the antiapoptotic genes, cellular inhibitor of apoptosis protein 2 (c-IAP2/HIAP-1/MIHC) is originally identified as a molecule recruited to the tumor necrosis factor (TNF) receptor complex, and its expression is preferentially up-regulated by TNF and other stimuli activating NF-κB. However, direct evidence of transcriptional regulation of NF-κB on the c-IAP2 gene is still missing. Here, we have cloned and characterized the promoter region required for NF-κB-dependent transcription of the c-IAP2gene. Sequencing of a 3.5-kilobase fragment of the 5′-flanking region of the c-IAP2 gene has identified a TATA-like sequence and potential binding sites for nuclear factor of activated T cells, interferon regulatory factor 1, activator protein 1, glucocorticoid response element, and three putative NF-κB binding elements. Deletion and mutational analysis of the 5′-flanking region linked to the luciferase gene revealed that transcriptional activation by TNF or interleukin 1 is mediated cooperatively by two NF-κB binding sites. Electrophoretic mobility shift assays characterized that the two NF-κB sites can be recognized and bound by the NF-κB p50/p65 heterodimer. In addition, the transcription of c-IAP2 promoter was strongly up-regulated when CD40 or Epstein-Barr virus latent membrane protein 1 was overexpressed.

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Published, JBC Papers in Press, April 6, 2000, DOI 10.1074/jbc.M001202200

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This work was supported by Genetic Engineering Grant 1998-019-F00041 from the Ministry of Education and by Korea Science and Engineering Foundation Grant 1999-0403-06-01-3.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) AF233684.

These authors contributed equally to this work.