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Type: Journal article
Title: Functional integrity of nuclear factor kB, 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?
Author: Zhou, J.
Callapina, M.
Goodall, G.
Brune, B.
Citation: Cancer Research, 2004; 64(24):9041-9048
Publisher: Amer Assoc Cancer Research
Issue Date: 2004
ISSN: 0008-5472
Abstract: Hypoxia-inducible factor (HIF)-1, a heterodimeric transcription factor composed of HIF-1alpha and HIF-1beta subunits coordinates pathophysiologic responses toward decreased oxygen availability. It is now appreciated that enhanced protein translation of HIF-1alpha under normoxia accounts for an alternative regulatory circuit to activate HIF-1 by hormones, growth factors, or cytokines such as tumor necrosis factor alpha (TNF-alpha). Here, we aimed at understanding molecular details of HIF-1alpha translation in response to TNF-alpha. In tubular LLC-PK(1) cells, activation of nuclear factor kappaB (NFkappaB) by TNF-alpha resulted in HIF-1alpha protein synthesis as determined by [(35)S]methionine pulse experiments. Protein synthesis was attenuated by blocking NFkappaB, phosphatidylinositol 3'-kinase (PI3k), and mitogen-activated protein kinase (MAPK). Use of a dicistronic reporter with the HIF-1alpha 5'-untranslated region (5'UTR) between two coding regions indicated that TNF-alpha promoted an internal ribosome entry site (IRES) rather than a cap-dependent translation. IRES-mediated translation required the functional integrity of the NFkappaB, PI3k, and MAPK signaling pathways. Although no signal cross-talk was noticed between NFkappaB, PI3k, and MAPK signaling, these pathways are needed to up-regulate the anti-apoptotic target protein Bcl-2 by TNF-alpha. Expression of Bcl-2 provoked not only IRES-dependent translation but also HIF-1alpha protein synthesis. We conclude that Bcl-2 functions as an important determinant in facilitating HIF-1alpha protein expression by TNF-alpha via an IRES-dependent translational mechanism. These observations suggest a link between Bcl-2 and HIF-1alpha expression, a situation with potential relevance to cancer biology.
Keywords: Cell Line
Tumor Necrosis Factor-alpha
NF-kappa B
Proto-Oncogene Proteins c-bcl-2
Transcription Factors
RNA, Messenger
MAP Kinase Signaling System
Protein Biosynthesis
Enzyme Activation
Hypoxia-Inducible Factor 1, alpha Subunit
Phosphatidylinositol 3-Kinases
DOI: 10.1158/0008-5472.CAN-04-1437
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