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THE 27 KD PROTEIN ENCODED BY THE HIV NEF GENE SHARES STRUCTURAL AND FUNCTIONAL HOMOLOGIES WITH SEVERAL ONCOGENE PRODUCTS
No full textThe HIV genome contains nine coding regions, whose function in viral replication is still partially unknown. One of these, nef (Negative factor, previously called 3'-orf or orf-B), encodes a 27 kilodalton protein (p27nef) inducing an early specific immune response in infected patients. p27nef resembles an oncogene product: (a) it is myristylated on the aminoterminal glycine and is therefore associated to the cell membrane; (b) it shares homologies with pp60src, with EGF receptor and with G protein GTP binding domain; (c) it is phosphorylated on serine and threonine residues in vivo; (d) it has a GTPase activity, and (e) it is autophosphorylated on a serine residue in vitro. The role of p27nef during viral replication is still controversial; his negative role on HIV growth has been recently debated. In this paper we analyse the primary structure of p27nef and its functional properties. Strong homologies with the proteins encoded by src, erb-B-1 and ras oncogenes suggest its possible interference with the transmembrane transduction of extracellular signalling
MONOCLONAL-ANTIBODIES AGAINST CELL-SURFACE ANTIGENS OF ROUS-SARCOMA VIRUS-TRANSFORMED FIBROBLASTS
No full textTHE 27 KD PROTEIN ENCODED BY THE HIV NEF GENE SHARES STRUCTURAL AND FUNCTIONAL HOMOLOGIES WITH SEVERAL ONCOGENE PRODUCTS
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Apoptosis enhancement by the HIV-1 Nef protein
Full text linkThe HIV-1 nef gene, essential for AIDS pathogenesis, encodes a 27-kDa protein (Nef) whose biochemical and biological functions are unclear. It has been suggested that Nef expression contributes to the T cell depletion observed during the disease by promoting their apoptosis. We report that in CD4+ human lymphoblastoid cell lines transfected with the nef cDNA obtained from three different HIV-1 strains, expression of the Nef protein enhances and accelerates the response to four unrelated apoptotic agents (staurosporine, anisomycin, camptothecin, and etoposide) but not to an anti-Fas agonist Ab. Nef reduces the expression of the anti-apoptotic proteins Bcl-2 and Bcl-XL and induces a striking enhancement of apoptotic hallmarks, including mitochondrial depolarization, exposure of phosphatidylserine on the cell surface, activation of caspase-3, and cleavage of the caspase target poly(ADP-ribose) polymerase. Interestingly, the peptide Z-Val-Ala-DL-Asp-fluoromethylketone (a broad-spectrum caspase inhibitor) reduces, but does not abolish, phosphatidylserine exposure, suggesting that Nef also activates a caspase-independent apoptotic pathway. Surprisingly, Nef expression increases DNA degradation but without causing oligonucleosomal fragmentation. An increased apoptotic response and down-modulation of Bcl-2/Bcl-XL following Nef expression are observed also in NIH-3T3 fibroblasts. These data show that Nef enhances programmed cell death in different cell types by affecting multiple critical components of the apoptotic machinery independently from the Fas pathway
Mutations in the met oncogene unveil a "dual switch" mechanism controlling tyrosine kinase activity
Full text linkThe met oncogene, encoding the high affinity hepatocyte growth factor receptor, is the only known gene inherited in human cancer that is invariably associated with somatic duplication of the mutant locus. Intriguingly, mutated Met requires ligand stimulation in order to unleash its transforming potential. Furthermore, individuals bearing a germ line met mutation develop cancer only late in life and with incomplete penetrance. To date, there is no molecular explanation for this unique behavior, which is unusual for a dominant oncogene. Here we investigate the molecular mechanisms underlying met oncogenic conversion by generating antibodies specific for the differently phosphorylated forms of the Met protein. Using these antibodies, we show that activation of wild-type Met is achieved through sequential phosphorylation of Tyr1235 and Tyr1234 in the activation loop and that mutagenesis of either tyrosine dramatically impairs kinase function. Surprisingly, oncogenic Met mutants never become phosphorylated on Tyr1234 despite their high enzymatic activity, and mutagenesis of Tyr1234 does not affect their biochemical or biological function. By analyzing the enzymatic properties of the mutant proteins in different conditions, we demonstrate that oncogenic mutations do not elicit constitutive kinase activation but simply overcome the requirement for the second phosphorylation step, thus reducing the threshold for activation. In the presence of activating signals, these mutations result therefore in a dynamic imbalance toward the active conformation of the kinase. This explains why mutant met provides an oncogenic predisposition but needs a second activating “hit,” provided by sustained ligand stimulation or receptor overexpression, to achieve a fully transformed phenotype
P145, A PROTEIN WITH ASSOCIATED TYROSINE KINASE-ACTIVITY IN A HUMAN GASTRIC-CARCINOMA CELL-LINE
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