Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice.
p19(ARF) is a key regulator of the p53-mediated apoptotic and tumor suppressor pathway. The proapoptotic Bax gene is a transcription target of p53, yet genetic studies in some animal models have suggested that Bax and p53 loss may cooperate in tumorigenesis. ARF-deficient mice are tumor prone, and to determine whether Bax loss could cooperate in the development of these tumors, we generated mice null for both ARF and Bax. The tumor latency of Bax+/+ARF-/-, Bax+/-ARF-/- and Bax-/-ARF-/- mice was similar with a mean survival of 48.9, 48.1, and 47.6 weeks, respectively. In Bax+/+ARF-/- mice, the predominant tumor type was B- and T-cell lymphoma followed by sarcomas and a lack of carcinomas. However, the frequency of lymphoma development dramatically decreased, whereas that of sarcomas and carcinomas increased, in a gene dosage-dependent manner in Bax+/-ARF-/- and Bax-/-ARF-/- mice. Furthermore, uncommon tumors of ARF-/- mice (osteosarcoma and hemangiosarcoma) were observed in Bax/ARF-double null mice, and tumor types not described previously in ARF-null mice (mixed germ cell tumor, Triton tumor, and histiocytic sarcoma) also developed in Bax-/-ARF-/- animals. Importantly, multiple primary malignant tumors of different lineage arose in 25% of the Bax-/-ARF-/- mice, whereas only one tumor type per animal was observed in Bax+/+ARF-null littermates. Finally, the wild-type Bax allele was retained in tumors arising in Bax+/-ARF-/- mice. Thus, Bax appears to function as a tumor modifier rather than as a classic tumor suppressor, and the combined loss of Bax and the ARF allows for the emergence of multiple malignant tumor types, an alteration of the tumor spectrum, and tumors not observed previously in ARF-null mice.
Eischen
Christine M
CM
Department of Biochemistry, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Rehg
Jerold E
JE
Korsmeyer
Stanley J
SJ
Cleveland
John L
JL
D000818:Animals; D019941:Cyclin-Dependent Kinase Inhibitor p16; D008223:Lymphoma / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2; D025803:Tumor Suppressor Protein p14ARF / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D051028:bcl-2-Associated X Protein
C494827:Bax protein, mouse; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025803:Tumor Suppressor Protein p14ARF; D051028:bcl-2-Associated X Protein