Loss of neurofibromatosis-1 and p19(ARF) cooperate to induce a multiple tumor phenotype.
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.
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Dana
D
King
Genyan
G
Yang
Mary Ann
MA
Thompson
Scott W
SW
Hiebert
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D016147:Genes, Tumor Suppressor; D051379:Mice; D009374:Neoplasms, Experimental / Q000209:etiology / Q000235:genetics* / Q000401:mortality; D016019:Survival Analysis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF