Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis

DeClue, Jeffrey E.; Papageorge, Alex G.; Fletcher, Jonathan A.; Diehl, Scott R.; Ratner, Nancy; Vass, William C.; Lowy, Douglas R.

doi:10.1016/0092-8674(92)90407-4

Cited by 543 publications

(352 citation statements)

References 45 publications

Supporting

Mentioning

326

Contrasting

Unclassified

Order By: Relevance

“…In support of this mechanism, several studies have shown that neuro®bromin suppresses cell growth by inhibiting p21-ras activity in some cell types. These results are consistent with the notion that the tumor suppressor function of neurofibromin is related to its ability to operate as a GAP molecule (Basu et al, 1992;DeClue et al, 1992;Bollag et al, 1996;Largaespada et al, 1996). However, little is known about the function of neuro®bromin in astrocytes relevant to the development of astrocytomas in individuals a ected with NF1.…”

Section: Introductionsupporting

confidence: 88%

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

et al. 1999

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionsupporting

confidence: 88%

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

et al. 1999

View full text Add to dashboard Cite

show abstract

“…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: 84%

“…Neuro®brosarcoma cell lines that do not express or that underexpress NF1, show decrease Ras-GTPase accelerating activity and higher levels of Ras-GTP than tumor cells with normal NF1 levels (Basu et al, 1992;DeClue et al, 1992). Primary cultures of myeloid leukemia show also a reduction in the NF1-like GAP activity and elevated levels of Ras-GTP after serum starvation, or GM-CSF or serum stimulation (Bollag et al, 1996;Largaespada et al, 1996).…”

Section: Mechanism Of Nf1 Tumor Suppressionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

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.

show abstract

“…This hypothesis has been formally proven by analysing the consequences of inactivating the NF1 tumor suppressor, the gene responsible for the familial cancer syndrome neurofibromatosis type I (NF1) (Courtois-Cox et al, 2006). NF1 encodes a RasGAP protein, and its inactivation has been shown to cause an acute activation of (endogenous) Ras and Ras effector pathways (Basu et al, 1992;DeClue et al, 1992). Similar to MEFs expressing a single activated K-ras allele, inactivation of NF1 via shRNA constructs results in the immortalization of this cell type (Courtois-Cox et al, 2006).…”

Section: Does Signal Intensity or Cell Type Matter?mentioning

confidence: 99%

Many roads lead to oncogene-induced senescence

2008

View full text Add to dashboard Cite

Abnormal regulation of mammalian p21ras contributes to malignant tumor growth in von Recklinghausen (type 1) neurofibromatosis

Cited by 543 publications

References 45 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

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

Many roads lead to oncogene-induced senescence

Contact Info

Product

Resources

About