Heidecker Gisela , Mood K, Ruscetti FW; International Conference on AIDS.
Int Conf AIDS. 1996 Jul 7-12; 11: 61 (abstract no. Mo.A.1041).
SAIC-NCI/FCRDC, Frederick, MD, USA. Fax: 301 846 7034. E-mail: heidecke@fcrfv1.ncifcrf.gov.
The nef gene of HIV and SIV has come into focus as a major contributor to the pathogenesis of primate immune deficiencies. Several lines of evidence suggest that Nef interferes with signal transduction in infected and possibly even in bystander cells. We have analyzed the interaction of SIV/Mne Nef protein with several proteins in the signal transduction network using co-precipitation of proteins expressed in the Sf9/baculovirus system as well as in mammalian cells. We have observed that Nef and Raf-1 interact. The interaction between Nef and Raf-1 is dependent on Nef myristoylation and involves the kinase domain of the Raf-1 protein. Raf-1 is a cytoplasmic serine threonine kinase which is activated in response to Ras stimulation and in turn phosphorylates MAP kinase kinase (MAPKK = Mek). As a consequence of Raf-1 activation the immediate early response of AP-1 dependent transcription is turned on. Raf-1 is a non-redundant point in the signal transduction network as knock out of Raf-1 activity by antisense oligos or by dominantnegative mutants is lethal to cells of all lineages tested. Expression of Nef in mammalian cells results in down-regulation of signalling components downstream of Raf such as MAP kinase and AP-1 and NFkB dependent transcription. In contrast, SIV/Mne Nef with an R18Y mutation activates signalling components downstream of Raf-1. This mutation has been shown previously by Du et al (Cell 82, 665, 1995) to greatly enhance the pathogenic potential of SIV/Mac. This down- or upregulation occurs in fibroblasts and lymphocytes suggesting that this effect is independent of Nef induced CD4 down-regulation.
Publication Types:
Keywords:
- Antigens, CD4
- Down-Regulation
- Gene Products, nef
- Genes, nef
- Genes, ras
- Mitogen-Activated Protein Kinase Kinases
- Protein-Serine-Threonine Kinases
- Proto-Oncogene Proteins
- Proto-Oncogene Proteins A-raf
- Proto-Oncogene Proteins c-raf
- Signal Transduction
- Simian immunodeficiency virus
- Transcription Factor AP-1
- genetics
- immunology
Other ID:
UI: 102217011
From Meeting Abstracts