Loss of neurofibromatosis-1 and p19^ARF cooperate to induce a multiple tumor phenotype

Abstract

Inactivation of the neurofibromatosis-1 (NF1) gene de-regulates RAS and cooperates with mutation or loss of the p53 tumor suppressor to induce tumorigenesis. p19^ARF acts upstream of p53 in an oncogene checkpoint to induce apoptosis in response to activated RAS and other factors that stimulate proliferation. Therefore, we bred p19^ARF−/− to NF1^+/− mice to determine if loss of these genes collaborates in tumorigenesis. As expected from the embryonic lethality of NF1 null mice, no mice lacking both p19^ARF and NF1 were born. Unexpectedly, the loss of one allele of NF1 did not greatly shorten the time to tumor formation in a p19^ARF null background. The tumor types observed were characteristic of p19^ARF null animals, not those associated with neurofibromatosis or those observed with NF1^+/−/p53^+/− mice. However, seven out of 12 animals developed multiple tumors, some with metastases. This multiple tumor phenotype was not previously observed with p19^ARF-null mice and suggests a distinct form of cooperation between the loss of these tumor suppressors.