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Functional Integrity of Nuclear Factor B, Phosphatidylinositol 3'-Kinase, and Mitogen-Activated Protein Kinase Signaling Allows Tumor Necrosis Factor -Evoked Bcl-2 Expression to Provoke Internal Ribosome Entry Site-Dependent Translation of Hypoxia-Inducible Factor 1

¹ Department of Cell Biology, Faculty of Biology, University of Kaiserslautern, Kaiserslautern, Germany; ² Division of Human Immunology and Hanson Institute, Institute of Medical and Veterinary Science, Adelaide, South Australia, Australia; and ³ Department of Medicine, The University of Adelaide, South Australia, Australia

Hypoxia-inducible factor (HIF)-1, a heterodimeric transcription factor composed of HIF-1 and HIF-1ß subunits coordinates pathophysiologic responses toward decreased oxygen availability. It is now appreciated that enhanced protein translation of HIF-1 under normoxia accounts for an alternative regulatory circuit to activate HIF-1 by hormones, growth factors, or cytokines such as tumor necrosis factor (TNF-). Here, we aimed at understanding molecular details of HIF-1 translation in response to TNF-. In tubular LLC-PK₁ cells, activation of nuclear factor B (NFB) by TNF- resulted in HIF-1 protein synthesis as determined by [³⁵S]methionine pulse experiments. Protein synthesis was attenuated by blocking NFB, phosphatidylinositol 3'-kinase (PI3k), and mitogen-activated protein kinase (MAPK). Use of a dicistronic reporter with the HIF-1 5'-untranslated region (5'UTR) between two coding regions indicated that TNF- promoted an internal ribosome entry site (IRES) rather than a cap-dependent translation. IRES-mediated translation required the functional integrity of the NFB, PI3k, and MAPK signaling pathways. Although no signal cross-talk was noticed between NFB, PI3k, and MAPK signaling, these pathways are needed to up-regulate the anti-apoptotic target protein Bcl-2 by TNF-. Expression of Bcl-2 provoked not only IRES-dependent translation but also HIF-1 protein synthesis. We conclude that Bcl-2 functions as an important determinant in facilitating HIF-1 protein expression by TNF- via an IRES-dependent translational mechanism. These observations suggest a link between Bcl-2 and HIF-1 expression, a situation with potential relevance to cancer biology.

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