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- Title
Signal transduction in hypoxic cells: inducible nuclear translocation and recruitment of theCBP/p300 coactivator by the hypoxia-induciblefactor-1a.
- Authors
Kallio, Pekka J.; Okamoto, Kensaku; O'Brien, Sallyann; Carrero, Pilar; Makino, Yuichi; Tanaka, Hirotoshi; Poellinger, Lorenz
- Abstract
In response to decreased cellular oxygen concentrations the basic helixloophelix (bHLH)/PAS (Per, Arnt, Sim) hypoxia-inducible transcription factor, HIF-1α, mediates activation of networks of target genes involved in angiogenesis, erythropoiesis and glycolysis. Here we demonstrate that the mechanism of activation of HIF-1α is a multi-step process which includes hypoxia-dependent nuclear import and activation (derepression) of the transactivation domain, resulting in recruitment of the CREB-binding protein (CBP)/p300 coactivator. Inducible nuclear accumulation was shown to be dependent on a nuclear localization signal (NLS) within the C-terminal end of HIF-1α which also harbors the hypoxia-inducible transactivation domain. Nuclear import of HIF-1α was inhibited by either deletion or a single amino acid substitution within the NLS sequence motif and, within the context of the full-length protein, these mutations also resulted in inhibition of the transactivation activity of HIF-1α and recruitment of CBP. However, nuclear localization per se was not sufficient for transcriptional activation, since fusion of HIF-1α to the heterologous GAL4 DNA-binding domain generated a protein which showed constitutive nuclear localization but required hypoxic stimuli for function as a CBP-dependent transcription factor. Thus, hypoxia-inducible nuclear import and transactivation by recruitment of CBP can be functionally separated from one another and play critical roles in signal transduction by HIF-1α.
- Subjects
CELLULAR signal transduction; TRANSPLANTATION of cell nuclei; TRANSCRIPTION factors; CARRIER proteins; AMINO acids; GENETIC regulation
- Publication
EMBO Journal, 1998, Vol 17, Issue 22, p6573
- ISSN
0261-4189
- Publication type
Article
- DOI
10.1093/emboj/17.22.6573