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Titolo:
Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo
Autore:
Ingram, DA; Yang, FC; Travers, JB; Wenning, MJ; Hiatt, K; New, S; Hood, A; Shannon, K; Williams, DA; Clapp, DW;
Indirizzi:
Indiana Univ, Sch Med, Canc Res Inst, Dept Pediat, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 Pediat, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Dept Microbiol & Immunol, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 mmunol, 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, Herman B Wells Ctr Pediat Res, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 at Res, Indianapolis, IN 46202 USA Indiana Univ, Sch Med, Howard Hughes Med Inst, Indianapolis, IN 46202 USA Indiana Univ Indianapolis IN USA 46202 d Inst, Indianapolis, IN 46202 USA Univ Calif San Francisco, Sch Med, Dept Pediat, San Francisco, CA 94143 USA Univ Calif San Francisco San Francisco CA USA 94143 ancisco, CA 94143 USA
Titolo Testata:
JOURNAL OF EXPERIMENTAL MEDICINE
fascicolo: 1, volume: 191, anno: 2000,
pagine: 181 - 187
SICI:
0022-1007(20000103)191:1<181:GABETH>2.0.ZU;2-E
Fonte:
ISI
Lingua:
ENG
Soggetto:
NEUROFIBROMATOSIS TYPE-1 GENE; MALIGNANT MYELOID DISORDERS; TYROSINE KINASE RECEPTOR; VONRECKLINGHAUSEN NEUROFIBROMATOSIS; BONE-MARROW; LOCUS; ALLELES; MUTATIONS; GROWTH; MOUSE;
Keywords:
c-kit; mast cell; heterozygous; neurofibromatosis; tumor suppressor;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
33
Recensione:
Indirizzi per estratti:
Indirizzo: Clapp, DW Indiana Univ, Sch Med, Canc Res Inst, Dept Pediat, 1044 W WalnutSt,Rm 421, Indianapolis, IN 46202 USA Indiana Univ 1044 W Walnut St,Rm 421Indianapolis IN USA 46202 A
Citazione:
D.A. Ingram et al., "Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo", J EXP MED, 191(1), 2000, pp. 181-187

Abstract

Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W andNf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions invivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W-41 mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligandfor c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras-mitogen-activated protein kinase activity, a major downstream effector ofRas, via wild-type and mutant (W-41) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 29/10/20 alle ore 21:27:48