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Titolo:
Identification of specific molecular structures of human immunodeficiency virus type 1 Tat relevant for its biological effects on vascular endothelial cells
Autore:
Mitola, S; Soldi, R; Zanon, I; Barra, L; Gutierrez, MI; Berkhout, B; Giacca, M; Bussolino, F;
Indirizzi:
IRCC, Inst Canc Res & Treatment, I-10060 Turin, Italy IRCC Turin Italy I-10060 Inst Canc Res & Treatment, I-10060 Turin, Italy Univ Turin, Sch Med, Dept Genet Biol & Biochem, I-10100 Turin, Italy Univ Turin Turin Italy I-10100 enet Biol & Biochem, I-10100 Turin, Italy Int Ctr Genet Engn & Biotechnol, Mol Med Lab, I-34012 Trieste, Italy Int Ctr Genet Engn & Biotechnol Trieste Italy I-34012 012 Trieste, Italy Univ Amsterdam, Acad Med Ctr, Dept Human Retrovirol, NL-1100 DE Amsterdam,Netherlands Univ Amsterdam Amsterdam Netherlands NL-1100 DE DE Amsterdam,Netherlands
Titolo Testata:
JOURNAL OF VIROLOGY
fascicolo: 1, volume: 74, anno: 2000,
pagine: 344 - 353
SICI:
0022-538X(200001)74:1<344:IOSMSO>2.0.ZU;2-I
Fonte:
ISI
Lingua:
ENG
Soggetto:
KAPOSIS-SARCOMA CELLS; LONG TERMINAL REPEAT; HIV-1 TAT; GROWTH-FACTOR; T-CELLS; BASIC DOMAIN; INDEPENDENT MECHANISM; MONOCYTE CHEMOTAXIS; MUTATIONAL ANALYSIS; FLK-1/KDR RECEPTOR;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
70
Recensione:
Indirizzi per estratti:
Indirizzo: Bussolino, F IRCC, Inst Canc Res & Treatment, Strada Provinciale 142,Km3-95, I-10060 Turin, Italy IRCC Strada Provinciale 142,Km3-95 Turin Italy I-10060 Italy
Citazione:
S. Mitola et al., "Identification of specific molecular structures of human immunodeficiency virus type 1 Tat relevant for its biological effects on vascular endothelial cells", J VIROLOGY, 74(1), 2000, pp. 344-353

Abstract

Human immunodeficiency virus type 1 (HIV-1) Tat transactivates viral genesand is released by infected cells, acting as a soluble mediator. In endothelial cells (EC), it activates a proangiogenic program by activating vascular endothelial growth factor receptor type 2 (VEGFR-2) and integrins. A structure-activity relationship study was performed by functional analysis of Tat substitution and deletion variants to define the Tar determinants necessary for EC activation, Variants were made (i) in the basic and (ii) in thecysteine-rich domains and (iii) in the C-terminaI region containing the RGD sequence required for integrin recognition. Our results led to the following conclusions. (i) Besides a high-affinity binding site corresponding to VEGFR-2, EC express low-affinity binding sites. (ii) The basic and the cysteine-rich variants bind only to the low-affinity binding sites and do not promote tyrosine phosphorylation of VEGFR-2. Furthermore, they have a reduced ability to activate EC in vitro, and they lack angiogenic activity. (iii)Mutants with mutations in the C-terminal region are partially defective for in vitro biological activities and in vivo angiogenesis, but they activate VEGFR-2 as Tat wild type. In conclusion, regions encoded by the first exon of tat are necessary and sufficient for activation of VEGFR-2. However, the C-terminaI region, most probably through RGD-mediated integrin engagement, is indispensable for full activation of an in vitro and in vivo angiogenic program.

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Documento generato il 12/07/20 alle ore 11:16:54