The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae

Xu, Guangwen; Lin, Boris K.; Tanaka, Kazuma; Dunn, Diane M.; Wood, Douglas R.; Gesteland, R. F.; White, Ray; Weiss, Robert B.; Tamanoi, Fuyuhiko

doi:10.1016/0092-8674(90)90149-9

Cited by 659 publications

(345 citation statements)

References 21 publications

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“…In addition to being mutated in tumors, Ras and NF1 are able to interact and function in the same proliferative pathway, suggesting a possible cooperating e ect for the deregulation of these two proteins in tumorigenesis. Consistent with this hypothesis is the observation that NF1 is able to downregulate ras in vitro (Martin et al, 1990;Xu et al, 1990) and to inhibit ras-dependent proliferative and transforming e ects in tissue culture by mechanisms dependent (Basu et al, 1992;DeClue et al, 1992;Bollag et al, 1996;Largaespada et al, 1996) and independent Johnson et al, 1993) of the Ras GTPase accelerating activity of NF1.…”

Section: Introductionmentioning

confidence: 85%

“…In addition, overexpression of full-length neurofibromin results in severe growth inhibition without an e ect on Ras-GTP levels in NIH3T3 cells (Johnson et al, 1994). (2) Neuro®bromin (or NF1-GRD) is able to inhibit the transforming or proliferative e ect of the ras oncogene, despite its inability to stimulate the GTPase activity of oncogenic Ras (Bollag & McCormick, 1991;Xu et al, 1990;Martin et al, 1990). For instance, full length NF1 or NF1-GRD suppresses tumorigenicity of the HCT116 human colon carcinoma cell line in nude mice (Li and White, 1996).…”

Section: Mechanism Of Nf1 Tumor Suppressionmentioning

confidence: 99%

“…In addition, we analysed the level of Ras-GTP in tumor tissue to study the dependence of this cooperative e ect on the Ras-GTPase accelerating activity of NF1. The evaluation of this mechanism was possible because we used transgenics which overexpress a wild type ras, rather than a ras oncogene, since only the wild type protein can be downregulated by NF1 (Bollag and McCormick, 1991;Xu et al, 1990;Martin et al, 1990).…”

Section: Introductionmentioning

confidence: 99%

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NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

et al. 1998

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We crossed transgenic mice overexpressing the N-ras proto-oncogene (RasTg) with mice carrying one inactivated copy of the NF1 tumor suppressor gene (NF1+/ 7) to assess their possible cooperation in tumorigenesis. We have found a signi®cant increase in the incidence of lymphomas in animals with both lesions (RasTg NF1+/ 7), as compared with animals with single lesions. The mechanism of this cooperation appears to be independent of the NF1 GTPase activating activity since the level of Ras-GTP in primary cultures of tumor tissue do not di er among animals with double and with single lesions. Nevertheless, the ®nding of signi®cantly higher levels of Erk-1 and Erk-2 activation in lymphomas in the RasTg NF1+/7 than in the RasTg group suggests that this cooperative e ect may be in part explained by increased signaling through the Erk pathways. Consistent with a role for Erk activation in transformation is the additional observation that Erk-1 and Erk-2 activation is signi®-cantly increased in lymphomas as compared with normal spleen. This activation is likely to occur by phosphorylation of previously synthesized and inactive Erk proteins since, despite di erences in activation, Erk-1 and Erk-2 expression is similar in normal and lymphoid tissue in all groups. The observed cooperation in in vivo lymphomagenesis between N-ras overexpression and NF1 inactivation emphasizes the importance of searching for additional functions for the NF1 protein and of intensifying the screening for NF1 mutations in human lymphomas.

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Section: Introductionmentioning

confidence: 85%

Section: Mechanism Of Nf1 Tumor Suppressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

et al. 1998

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“…These proteins can act as negative regulators of the protooncogene product Ras by facilitating the GTPase activity of Ras and thus increasing the proportion of the inactivated GDP-bound form of Ras in a cell (Bollag and McCormick, 1991). GAP-like enzymatic activity has been demonstrated for neurofibromin (Ballester et al, 1990;Martin et al, 1990;Xu et al, 1990a). Support for in vivo interaction between neurofibromin and Ras has come from recent studies showing that increased levels of Ras-GTP are correlated with decreases in neurofibromin in NF1 related Schwann cell tumors (Basu et al, 1992;DeClue et al, 1992).…”

Section: Introductionmentioning

confidence: 99%

Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development

Daston

Ratner

1992

Developmental Dynamics

107

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The onset of manifestations of the common, autosomal dominantly inherited disease type 1 neurofibromatosis (NFl) is usually in childhood. To begin to understand the pathogenesis of NF1, we analyzed the developmental pattern of expression of the protein product of the NF1 gene, neurofibromin, by Western blotting and immunohistochemistry using the rat as a model system. Neurofibromin is uniformly distributed throughout embyronic day 10 and 12 rat embryos. By embryonic day 16, neurofibromin immunoreactivity is enriched in neurons of the cortical plate, in peripheral ganglia, and in developing CNS and PNS fiber tracts, but remains detectable outside the nervous system. Expression decreases in nonneural tissues by postnatal day 6, and neurofibromin is greatly decreased (lung, adrenal cortex, skin) or absent (skeletal muscle, cartilage) in adult tissues except for brain, spinal cord, peripheral nerve, and adrenal medulla. Transient expression of neurofibromin during development in many tissues suggests the importance of this GTPase-activating protein in morphogenesis and organ growth. A separate role is proposed for neurofibromin in growing axons and in the mature nervous system. 0 1993 Wiley-Liss, Inc.

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“…A 360 amino acid region of neurofibromin shows significant homology to the catalytic domain of the mammalian p21 ras-specific 120-kDa GTPase-activating protein (p120 GAP), yeast equivalents IRAI and IRA2 proteins and recently identified mammalian p21 ras-specific GAPs (Ballester et al, 1990;Maekawa et al, 1994;Weisbach et al, 1994;Baba et al, 1995). This GAP-related domain (GRD) of neurofibromin, as well as the full-length neurofibromin, can negatively regulate p21 ras in vitro by stimulating its weak intrinsic GTPase activity (Xu et al, 1990;Golubic et al, 1992).…”

mentioning

confidence: 99%

Reduced expression of neurofibromin in human meningiomas

Sundaram

Lee²,

Harwalkar³

et al. 1997

Br J Cancer

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Summary Meningiomas are common, mostly benign, tumours arising from leptomeningeal cells of the meninges, which frequently contain mutations in the neurofibromatosis type 2 (NF2) gene. In this study, we analysed a protein product of the neurofibromatosis type 1 (NF1) gene, neurofibromin, in human established leptomeningeal cells LTAg2B, in 17 sporadic meningiomas and in a meningioma from a patient affected by NF2. The expression level of neurofibromin was determined by immunoblotting and immunoprecipitation with anti-neurofibromin antibodies. The functional status of neurofibromin was analysed through its ability to stimulate the intrinsic GTPase activity of p21 ras. In the cytosolic extracts of four sporadic meningiomas and in the NF2-related meningioma, the expression level and the GTPase stimulatory activity of neurofibromin were drastically reduced compared with the level present in the human brain, human established leptomeningeal cells LTAg2B and the remaining 13 meningiomas. Our results suggest that neurofibromin is expressed in leptomeningeal cells LTAg2B and in most meningiomas, i.e. tumours derived from these cells. The reduced expression and GTPase stimulatory activity of neurofibromin was found in about 23% of meningiomas and in the single NF2-related meningioma analysed. These results suggest that decreased levels of neurofibromin in these tumours may contribute to their tumorigenesis.

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The catalytic domain of the neurofibromatosis type 1 gene product stimulates ras GTPase and complements ira mutants of S. cerevisiae

Cited by 659 publications

References 21 publications

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

NF1 inactivation cooperates with N-Ras in in vivo lymphogenesis activating Erk by a mechanism independent of its Ras-GTPase accelerating activity

Neurofibromin, a predominantly neuronal GTPase activating protein in the adult, is ubiquitously expressed during development

Reduced expression of neurofibromin in human meningiomas

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