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Titolo:
Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro
Autore:
Ingram, DA; Hiatt, K; King, AJ; Fisher, L; Shivakumar, R; Derstine, C; Wenning, MJ; Diaz, B; Travers, JB; Hood, A; Marshall, M; Williams, DA; Clapp, DW;
Indirizzi:
Indiana Univ, Sch Med, Herman B Wells Ctr Pediat Res, Canc Res Inst, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 s Inst, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Pediat, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 Pediat, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Immunol Microbiol, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 robiol, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Dermatol, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 rmatol, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Med, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 pt Med, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Mol Genet, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 Genet, Indianapolis, IN 46202 USA Howard Hughes Med Inst, Indianapolis, IN 46202 USA Howard Hughes Med InstIndianapolis IN USA 46202 dianapolis, IN 46202 USA Eli Lilly & Co, Indianapolis, IN 46285 USA Eli Lilly & Co Indianapolis INUSA 46285 & Co, Indianapolis, IN 46285 USA
Titolo Testata:
JOURNAL OF EXPERIMENTAL MEDICINE
fascicolo: 1, volume: 194, anno: 2001,
pagine: 57 - 69
SICI:
0022-1007(20010702)194:1<57:HOPATH>2.0.ZU;2-Y
Fonte:
ISI
Lingua:
ENG
Soggetto:
C-KIT LIGAND; PROTEIN-KINASE; PHOSPHATIDYLINOSITOL 3-KINASE; ACTIVATION; RAS; NF1; RECEPTOR; PAK; CARCINOGENESIS; PATHWAYS;
Keywords:
Rac; Pak; PI3-K; cross-talk; neurofibromatosis type 1;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
46
Recensione:
Indirizzi per estratti:
Indirizzo: Clapp, DW Indiana Univ, Sch Med, Herman B Wells Ctr Pediat Res, Canc Res Inst, 1044 W Walnut,Rm 408, Indianapolis, IN 46202 USA Indiana Univ 1044 W Walnut,Rm 408 Indianapolis IN USA 46202 USA
Citazione:
D.A. Ingram et al., "Hyperactivation of p21(ras) and the hematopoietic-specific Rho GTPase Rac2, cooperate to alter the proliferation of neurofibromin-deficient mast cells in vivo and in vitro", J EXP MED, 194(1), 2001, pp. 57-69

Abstract

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients of Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21(ras) activity by accelerating the conversion of Ras-GTPto Ras-GDP. However, identification of alterations in specific P21(ras) effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21(ras) may depend on signaling outputs from small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1(+/-) and Rac2(-/-) mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal-regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstratethat Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21(ras)-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1(+/-) mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21(ras)-ERK pathway which function to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.

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Documento generato il 25/09/20 alle ore 20:27:45