‘In Vivo’ Model Systems to Study ras Oncogene Involvement in Carcinogenesis

Mangues, Ramón; Pellicer, Ángel Antonio Blasco

doi:10.1007/978-1-4615-3056-5_9

Cited by 9 publications

(12 citation statements)

References 33 publications

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“…It has been reported that over-expression of any of three normal Ras genes, N-Ras (McKay et al, 1986), H-Ras (Westaway et al, 1986;Zhang et al, 1997) or K-Ras (George et al, 1986) leads to in vitro transformation. In vivo, overexpression of normal N-Ras is associated with development of hyperplasia and tumors in transgenic mice (Mangues et al, 1992). Here, we show for the ®rst time that over-expression of normal M-Ras induces melanocyte transformation in vitro.…”

Section: Discussionmentioning

confidence: 60%

MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression

Wang

Yang

et al. 2000

Oncogene

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The MGSA/GRO protein is endogenously expressed in almost 70% of the melanoma cell lines and tumors, but not in normal melanocytes. We have previously demonstrated that over-expression of human MGSA/GROa, b or g in immortalized murine melanocytes (melan-a cells) enables these cells to form tumors in SCID and nude mice. To examine the possibility that the MGSA/GRO eect on melanocyte transformation requires expression of other genes, dierential display was performed. One of the mRNA's identi®ed in the screen as overexpressed in MGSA/GRO transformed melan-a clones was the newly described M-Ras or R-Ras3 gene, a member of the Ras gene superfamily. Over-expression of MGSA/GRO upregulates M-Ras expression at both the mRNA and protein levels, and this induction requires an intact glutamine-leucine-arginine (ELR)-motif in the MGSA/ GRO protein. Western blot examination of Ras expression revealed that K-and N-Ras proteins are also elevated in MGSA/GRO-expressing melan-a clones, leading to an overall increase in the amount of activated Ras. MGSA/GRO-expressing melan-a clones exhibited enhanced AP-1 activity. The eects of MGSA/GRO on AP-1 activation could be mimicked by over-expression of wild-type M-Ras or a constitutively activated M-Ras mutant in control melan-a cells as monitored by an AP-1-luciferase reporter, while expression of a dominant negative M-Ras blocked AP-1-luciferase activity in MGSA/GRO-transformed melan-a clones. In the in vitro transformation assay, over-expression of M-Ras mimicked the eects of MGSA/GRO by inducing cellular transformation in control melan-a cells, while over-expression of dominant negative M-Ras in MGSA/ GROa-expressing melan-a-6 cells blocked transformation. These data suggest that MGSA/GRO-mediated transformation requires Ras activation in melanocytes.

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Section: Discussionmentioning

confidence: 60%

MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression

Wang

Yang

et al. 2000

Oncogene

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“…They overexpress the MMTV/N-ras N transgene (N-ras proto-oncogene under the control of the MMTV-LTR promoter) (described in Mangues et al, 1992; and are heterozygous knockout for the NF1 (described in Jacks et al, 1994). (2) RasTg group: 45 mice which overexpress the MMTV/N-ras N transgene and are wild type for NF1.…”

Section: Resultsmentioning

confidence: 99%

“…These transgenic lines were previously generated; one carrying the N-ras proto-oncogene under the mouse mammary tumor virus promoter (previously referred to as MMTV/N-ras N and here described with the shorter acronym: RasTg) predisposes to lymphoid and mammary tumors (Mangues et al, 1992(Mangues et al, , 1994(Mangues et al, , 1996 and the other (referred to as NF1+/7) predisposes mainly to lymphoma, pheochromocytoma and lung adenocarcinomas (Jacks et al, 1994). We have found an increased incidence of lymphomas in animals with both N-Ras and NF1 lesions, as compared with animals with single lesions.…”

Section: Introductionmentioning

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

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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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“…The ras oncogenes (including H-, K-and N-ras), which are activated by point mutations, are implicated in carcinogenesis (reviewed in Barbacid, 1990;Rodenhuis, 1992). About 30% of all human tumors are associated with ras mutations and up to 95% of human pancreatic cancers contain K-ras mutations (Mangues and Pellicer, 1992;Rodenhuis, 1992). Ras proteins play central roles in receptor-mediated signal transduction pathways that control cell proliferation and di erentiation (Khosravi-Far and Der, 1994;Medema and Bos, 1993).…”

Section: Introductionmentioning

confidence: 99%

K-ras modulates the cell cycle via both positive and negative regulatory pathways

Fan

Bertino

1997

Oncogene

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‘In Vivo’ Model Systems to Study ras Oncogene Involvement in Carcinogenesis

Cited by 9 publications

References 33 publications

MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression

MGSA/GRO-mediated melanocyte transformation involves induction of Ras expression

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

K-ras modulates the cell cycle via both positive and negative regulatory pathways

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