The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21

Martin, George A.; Viskoohil, David; Bollag, Gideon; McCabe, Peter C.; Crosier, Walter J.; Haubruck, Heinz; Conroy, Leah; Clark, Robin; O’Connell, P.; Cawthon, Richard M.; Innis, Michael A.; McCormick, Frank

doi:10.1016/0092-8674(90)90150-d

Cited by 911 publications

(514 citation statements)

References 38 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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“…Neuro®bromin is expressed in many cell types and tissues, including neurons, astrocytes, Schwann cells, oligodendrocytes, blood vessels, adrenal medulla, gonadal tissues, and white blood cells (DeClue et al, 1991;Gutmann et al, 1991Gutmann et al, , 1995Daston et al, 1992;Golubic et al, 1992;Datson and Ratner, 1993;Huynh et al, 1992). Sequence analysis demonstrated that a small central domain of neuro®bromin shares similarity with the catalytic domain of proteins involved in p21-ras regulation (Ballester et al, 1990;Martin et al, 1990;Xu et al, 1990a,b). These GTPase-activating proteins (GAPs) function to accelerate the inactivation of the p21-ras protein from its active GTP-bound to its inactive GDP-bound form (Bollag and McCormick, 1991).…”

Section: Introductionmentioning

confidence: 99%

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

et al. 1999

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Individuals a ected with neuro®bromatosis 1 (NF1) harbor increased numbers of GFAP-immunoreactive cerebral astrocytes and develop astrocytomas that can lead to blindness and death. Mice heterozygous for a targeted Nf1 mutation (Nf1+/7) were employed as a model for the human disease to evaluate the hypothesis that reduced NF1 protein (neuro®bromin) expression may confer a growth advantage for astrocytes, such that inactivation of only one NF1 allele is su cient for abnormal astrocyte proliferation. Here, we report that Nf1+/7 mice have increased numbers of cerebral astrocytes and increased astrocyte proliferation compared to wild-type littermates. Intriguingly, primary Nf1+/7 astrocyte cultures failed to demonstrate a cell-autonomous growth advantage unless they were cocultured with C17 neuronal cells. This C17 neuronal cellinduced Nf1+/7 increase in proliferation was blocked by MEK inhibition (PD98059), suggesting a p21-rasdependent e ect. Furthermore, mice heterozygous for a targeted mutation in another GAP molecule, p120-GAP, demonstrated no increases in cerebral astrocyte number. These ®ndings suggest that reduced NF1 expression results in a cell context-dependent increase in astrocyte proliferation that may be su cient for the development of astrocytic growth abnormalities in patients with NF1.

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“…Introduction into schwannoma cell lines of cDNA encoding the GAP induced morphological reversion of the cells and decreased the proportion of GTP-bound ras (DeClue et al, 1992). It has been proposed that the NF1 GRD product suppresses malignant tumor growth by interacting with ras proteins and accelerating ras GTPase activity (DeClue et al, 1992;Martin et al, 1990).…”

mentioning

confidence: 99%

Differential expression of NF1 type I and type II isoforms in sporadic borderline and invasive epithelial ovarian tumors

Iyengar

Lau

et al. 1999

Oncogene

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The NF1 gene, a putative tumor suppressor gene, contains a GAP related domain (GRD) which accelerates hydrolysis of ras-bound GTP to GDP, thereby converting the ras oncogene from its active to inactive form. Two forms of the NF1 GRD transcript (Type I and Type II) are di erentially expressed in neuroectodermal tumor tissue relative to di erentiated neural cells, and in gastric cancer cell lines relative to normal stomach mucosa. We measured relative expression of NF1 Type II and Type I isoforms in cultured normal and malignant human ovarian surface epithelial cells(HOSE) and in invasive and borderline ovarian tumor tissue. We demonstrated an 11-fold increase in Type II: Type I ratio in 7 HOSE cultures relative to eight ovarian cancer cell lines. Our ®ndings indicate a signi®cant decrease in Type II isoform expression and increase in Type I expression in ovarian cancer cells and tumor tissue relative to HOSE cells. We also demonstrate an increase in Type II: Type I ratio, and a decrease in cell proliferation rate in three ovarian cancer cell lines on treatment with retinoic acid. We propose that di erential expression of the NF1 Type I and Type II isoforms is related to cellular di erentiation in ovarian epithelial cancer and strategies based on alteration in NF1 isoform expression may have therapeutic potential in ovarian malignancies.Keywords: ovary; cancer; NF1; retinoic acid Ovarian cancer is the ®fth most common cancer and the fourth leading cause of cancer death among women in the United States. It is the leading cause of death by gynecologic malignancy. While much of our understanding of the genetic basis of ovarian cancer remains speculative, evidence indicates that development of ovarian tumors requires a series of genetic changes involving dominant oncogenes, mismatch repair genes, and a large number of tumor suppressor genes (Cliby et al

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The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21

Cited by 911 publications

References 38 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

Haploinsufficiency for the neurofibromatosis 1 (NF1) tumor suppressor results in increased astrocyte proliferation

Differential expression of NF1 type I and type II isoforms in sporadic borderline and invasive epithelial ovarian tumors

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