NF1 INACTIVATION COOPERATES WITH N-RAS IN IN-VIVO LYMPHOGENESIS ACTIVATING ERK BY A MECHANISM INDEPENDENT OF ITS RAS-GTPASE ACCELERATING ACTIVITY

We crossed transgenic mice overexpressing the N-ras proto-oncogene (Ra sTg) with mice carrying one inactivated copy of the NF1 tumor suppress or gene (NF1+/-)to assess their possible cooperation in tumorigenesis. We have found a significant increase in the incidence of lymphomas in animals with both lesions (RasTg NF1+/-), as compared with animals wi th single lesions, The mechanism of this cooperation appears to be ind ependent of the NF1 GTPase activating activity since the level of Ras- GTP in primary cultures of tumor tissue do not differ among animals wi th double and with single lesions. Nevertheless, the finding of signif icantly higher levels of Erk-1 and Erk-2 activation in lymphomas in th e RasTg NF1+/- than in the RasTg group suggests that this cooperative effect 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 sign ificantly increased in lymphomas as compared with normal spleen. This activation is likely to occur by phosphorylation of previously synthes ized and inactive Erk proteins since, despite differences in activatio n, Erk-1 and:Erk-2 expression is similar in normal and lymphoid tissue in all groups. The observed cooperation in in vivo lymphomagenesis be tween N-ras overexpression and NF1 inactivation emphasizes the importa nce of searching for additional functions for the NF1 protein and of i ntensifying the screening for NF1 mutations in human lymphomas.