title: Both products of the mouse Ink4a/Arf locus suppress melanoma formation in vivo.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street (M413), Boston, MA 02115, USA.
authors.forename: Norman Edward
authors.initials: NE
authors.lastname: Sharpless
authors.forename: Karuppiah
authors.initials: K
authors.lastname: Kannan
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.forename: Marcus Wolfram
authors.initials: MW
authors.lastname: Bosenberg
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
mesh_terms: 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*
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF