The neurofibromatosis type 1 gene encodes a protein related to GAP

Xu, Guangwen; O’Connell, P.; Viskochil, David; Cawthon, Richard M.; Robertson, Margaret; Culver, Melanie; Dunn, Diane M.; Stevens, Jeff; Gesteland, R. F.; White, Ray; Weiss, Robert B.

doi:10.1016/0092-8674(90)90024-9

Cited by 1,043 publications

(525 citation statements)

References 34 publications

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“…In its GTP-bound form, Ras is activated, resulting in the downstream activation of numerous signal transduction pathways. Ras.GTP is rapidly inactivated to Ras.GDP through an intrinsic GTPase activity, catalyzed by GTPase Activating Proteins (Ras-GAPs), predominantly p120-GAP and neuro®bromin, the protein product of the NF1 gene (Downward, 1992;Xu et al, 1990). Oncogenic Ras is resistant to RasGAPs (Barbacid, 1987), and is thus locked in its GTPbound form, resulting in constitutive activation of the protein and persistent activation of downstream pathways.…”

Section: Introductionmentioning

confidence: 99%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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While 25% of human cancers harbor oncogenic Ras mutations, such mutations are not found in astrocytomas. We have previously demonstrated that the activation of receptor tyrosine kinases expressed by malignant human astrocytoma cells and specimens results in functional upregulation of the Ras signalling pathway and increased levels of activated Ras.GTP. Farnesyl transferase inhibitors (FTIs) are promising anti-cancer agents in early clinical trials, which may exert their e ect through pharmacological inhibition of the Ras signalling pathway. In this study we establish the anti-tumorigenic properties of the FTI L-744,832 against a panel of malignant human astrocytoma cell lines. Furthermore, we demonstrate the multiple mechanisms by which L-744,832 exerts its e ect. L-744,832 demonstrates both cytostatic and cytotoxic e ects on astrocytoma cells, and cells expressing a truncated constitutively phosphorylated Epidermal Growth Factor Receptor common in highgrade astrocytomas (EGFRvIII/p140 EGF-R ) demonstrate increased sensitivity to the agent. L-744,832 is capable of inducing apoptosis in astrocytoma cells under anchoragedependent conditions; this process occurs in a p53-independent manner and is associated with increased expression of Bax and Bak. L-744,832 also induces cell cycle arrest at both the G 1 /M and G 2 /S checkpoints; this process is also independent of p53 mutational status. Cell cycle arrest in drug-treated cells can be accompanied by induction of p21 WAF1/CIP1 , but this induction is not necessary for the cell cycle inhibitory e ects, nor is it dependent on functional p53. Finally, angiogenesis in astrocytomas has been shown to be dependent on secretion of Vascular Endothelial Growth Factor (VEGF) by tumour cells, particularly under hypoxic conditions. L-744,832 potently inhibits the secretion of VEGF under hypoxic conditions. These combinations of mechanisms suggest that these tumours, despite the absence of oncogenic Ras mutations, will be amenable to growth inhibition by FTIs, through a combination of anti-proliferative, pro-apoptotic, and anti-angiogenic e ects.

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Section: Introductionmentioning

confidence: 99%

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

1999

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“…Analysis of the predicted protein sequence of the NF1 gene product (neurofibromin) revealed that a 360-amino acid region in the center of the protein has significant homology with a family of the GTPase-activating proteins (GAPs) including mammalian ras-GAP, budding yeast IRA1 and IRA2, fission yea~[-sarl, and Drosophila GAPI [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP‐dependent protein kinase

1996

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The critical function of the neurofibromatosis type 1 lyzed, As a clue to elucidate further the function of neurofi-(NFI) gene product (neurofibromin) is not well defined except bromin, we directed our attention to reports suggesting that that neurofibromin has homology with a family of the GTPaseneurofibromin is heavily phosphorylated on serine and threoactivating proteins (GAPs). In this study, we confirmed that nine resiid~ues in response to growth factors [3,18]. In this neurofibromin is constitutively phosphorylated and detected study, we detected kinase activities which specifically phoskinase activities which specifically phosphorylate the eysteinl phorylate neurofibromin in cell extracts and defined that serine-rich domain and fhe C-terminal domain of the neuroficAMP-dependent protein kinase (PKA) is a candidate for hromin in cell lysate. In vitro and in-gel kinase assays strongly the neurofibromin kinase. indicated that cAMP-dependent protein kinase (PKA) is a candidate for the neurofibromin kinase. The biolo,.ical significance of the phosphorylation of neurofibromin is unclear at present, but we speculate that neurofibromin plays a crucial role in cellular function since it links the two major cellular pathways which are the GAP..rns and PKA-assnciated signals.

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“…The NF1 gene contains a region, the NF1 GAP related domain (GRD), which is similar in function and sequence to catalytic domains of the mammalian GTPase activating protein (GAP) (Xu et al, 1990) and to yeast IRA proteins (Tanaka et al, 1990), both of which mediate the hydrolysis of ras-bound GTP which is an active form of ras to an inactive GDP-bound form (McCormick et al, 1988;Vogel et al, 1988). Schwannoma cell lines expressing low levels of NF1 protein product contain abnormally high levels of active GTP-bound ras.…”

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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 neurofibromatosis type 1 gene encodes a protein related to GAP

Cited by 1,043 publications

References 34 publications

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Growth inhibition of astrocytoma cells by farnesyl transferase inhibitors is mediated by a combination of anti-proliferative, pro-apoptotic and anti-angiogenic effects

Phosphorylation of neurofibromatosis type 1 gene product (neurofibromin) by cAMP‐dependent protein kinase

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

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