Proliferation of human malignant astrocytomas is dependent on Ras activation

Guha, Abhijit; Feldkamp, Matthias M.; Lau, Nelson C.; Boss, Gerry R.; Pawson, A.

doi:10.1038/sj.onc.1201455

Cited by 292 publications

(230 citation statements)

References 57 publications

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“…One of the most common alterations observed in high grade gliomas is increased activation of p21-ras Guha et al, 1997). In the case of sporadic astrocytomas, this increase in p21-ras activity results from abnormal activation of the positive regulators of p21-ras, as a consequence of augmented EGF-R signaling (Guha et al, 1997). Activation of the EGF-R results in recruitment of the shc adaptor protein and the hSOS guanosine nucleotide replacing factor (GNRF), culminating in activation of p21-ras by the exchange of GDP for GTP.…”

Section: Discussionmentioning

confidence: 99%

“…Previous work from our laboratory and others has demonstrated that increased p21-ras activity is a common feature of sporadic malignant astrocytomas Guha et al, 1997). Inhibition of p21-ras activity in astrocytoma tumor cells results in reduced cell proliferation both in vitro and in vivo (Guha et al, 1997).…”

Section: Introductionmentioning

confidence: 95%

“…Inhibition of p21-ras activity in astrocytoma tumor cells results in reduced cell proliferation both in vitro and in vivo (Guha et al, 1997). The increase in p21-ras activation in astrocytomas is the direct result of altered signaling through the epidermal growth factor receptor (EGF-R), such that more p21-ras is converted from the inactive GDP to the active GTP bound conformation.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

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

et al. 1999

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“…We measured Rasbound GTP and GDP by a relatively new enzymatic method (Guha et al, 1996(Guha et al, , 1997Scheele et al, 1995). This method has the advantage of assessing the absolute amounts of GTP and GDP bound to Ras.…”

Section: Discussionmentioning

confidence: 99%

Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice

et al. 1998

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We have previously documented that transgenic mice expressing SV40 Tag regulated by the rat prostatic steroid-binding protein C3(1) 5'-¯anking region display multistage mammary tumorigenesis. To delineate genetic changes associated with mammary tumor progression, comparative genomic hybridization (CGH) was performed. CGH revealed a consistent gain of the telomeric region of chromosome 6. This region contains the Ki-ras proto-oncogene. Analyses of genomic DNA by Southern blot demonstrated up to 40-fold ampli®cation of the Kiras gene. Ki-ras ampli®cation was detected in 12, 46 and 68% of tumors from 4, 5 and 6 month old mice, respectively, whereas no ampli®cations were found in any preneoplastic mammary tissues. Tumors bearing Ki-ras gene ampli®cation exhibited high levels of Ki-ras RNA and protein. The over-expressed Ki-Ras protein in these tumors appeared functionally active as indicated by the elevated MAP kinase activity. These data demonstrate that while Ki-ras ampli®cation might not be an early event, there is a strong association between Ki-ras ampli®cation and over-expression and mammary tumor progression in this model. This study also shows that CGH is a powerful and useful technique for identifying chromosomal copy number changes during tumor progression, and that this model may provide a predictable in vivo system for studying gene ampli®ca-tion.

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“…Among the 4 cell lines analyzed, U87cells had been described to contain large amount (around 30%) of the total Ras in the GTP bound state. 18 Radioresistant U87 cells were stably transfected with pGRE.2-RasN17 and the presence of an inducible RasN17 protein was tested in the selected clones. Out of the 5 clones selected, 2 presented an inducible expression of RasN17 after treatment with 25 nM dexamethasone for 48 hr (Fig 4a).…”

Section: Implication Of Ras In Glioma Radioresistancementioning

confidence: 99%

Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation

Delmas

Heliez

Cohen–Jonathan

et al. 2002

Intl Journal of Cancer

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We investigated for the first time the ability of farnesyltransferase inhibitors (FTI) to radiosensitize human glioma. For this, human glioma cell lines were treated with the specific FTI, R115777, 48 hr prior to a 2Gy irradiation. The treatment with R115777 decreased by 45% the SF2 value of the more radioresistant glioma cell lines (SF763 and U87) without any significant effect on the radioresistance of the radiosensitive ones (SF767 and U251-MG). This radiosensitizer effect was due to the induction of post-mitotic necrotic cell death. We then tested the hypothesis that wild-type Ras or RhoB, which has been proposed as potential FTI target, could control the glioma radioresistance. For this, we expressed inducible dominant negative forms of Ras (RasN17) and RhoB (RhoBN19) in radioresistant U87 glioma cell line and analyzed the survival after irradiation of the obtained clones. While blocking Ras pathways by expression of RasN17 did not affect the SF2 value of the U87 glioma cell line, the expression of RhoBN19 dramatically reduced the cell survival after irradiation of these cells. Taken together, these data demonstrated that RhoB, but not Ras, is implicated in glioma radioresistance. Furthermore, the R115777 differential radiosensitizer effect underlines the potential therapeutic interest of using this drug as a radiosensitizer of human glioma.

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Proliferation of human malignant astrocytomas is dependent on Ras activation

Cited by 292 publications

References 57 publications

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

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

Amplification of Ki-ras and elevation of MAP kinase activity during mammary tumor progression in C3(1)/SV40 Tag transgenic mice

Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation

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