Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo.
Deletion of the INK4a/ARF locus at 9p21 is detected with high frequency in human melanoma. Within a short genomic distance, this locus encodes several proteins with established tumor-suppressor roles in a broad spectrum of cancer types. Several lines of evidence support the view that p16INK4a and p19ARF exert the tumor-suppressor activities of this locus, although their relative importance in specific cancer types such as melanoma has been less rigorously documented on the genetic level. Here, we exploit a well-defined mouse model of RAS-induced melanomas to examine the impact of germline p16INK4a or p19ARF nullizygosity on melanoma formation. We demonstrate that loss of either Ink4a/Arf product can cooperate with RAS activation to produce clinically indistinguishable melanomas. In line with the common phenotypic end point, we further show that RAS+ p16INK4a-/- melanomas sustain somatic inactivation of p19ARF-p53 and, correspondingly, that RAS+ p19ARF-/- melanomas experience high-frequency loss of p16INK4a. These genetic studies provide definitive proof that p16INK4a and p19ARF cooperate to suppress the development of melanoma in vivo.
Sharpless
Norman Edward
NE
Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street (M413), Boston, MA 02115, USA.
Kannan
Karuppiah
K
Xu
Jin
J
Bosenberg
Marcus Wolfram
MW
Chin
Lynda
L
D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism*; D008545:Melanoma / Q000378:metabolism*; D051379:Mice; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism*
C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF