title: A melanoma-associated germline mutation in exon 1beta inactivates p14ARF.
abstract: The INK4a/ARF locus encodes the cyclin dependent kinase inhibitor, p16(INK4a) and the p53 activator, p14ARF. These two proteins have an independent first exon (exon 1alpha and exon 1beta, respectively) but share exons 2 and 3 and are translated in different reading frames. Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Although most of these mutations specifically inactivate p16(INK4a), more than 40% of the INK4a/ARF alterations located in exon 2, affect both p16(INK4a) and p14ARF. We now report a 16 base pair exon 1beta germline insertion specifically altering p14ARF, but not p16(INK4a), in an individual with multiple primary melanomas. This mutant p14ARF, 60ins16, was restricted to the cytoplasm, did not stabilize p53 and was unable to arrest the growth of a p53 expressing melanoma cell line. This is the first example of an exon 1beta mutation that inactivates p14ARF, and thus implicates a role for this tumour suppressor in melanoma predisposition.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney, Westmead Hospital, Westmead NSW 2145, Australia. helen_rizos@wmi.usyd.edu.au
authors.forename: H
authors.initials: H
authors.lastname: Rizos
authors.forename: S
authors.initials: S
authors.lastname: Puig
authors.forename: C
authors.initials: C
authors.lastname: Badenas
authors.forename: J
authors.initials: J
authors.lastname: Malvehy
authors.forename: A P
authors.initials: AP
authors.lastname: Darmanian
authors.forename: L
authors.initials: L
authors.lastname: Jiménez
authors.forename: M
authors.initials: M
authors.lastname: Milà
authors.forename: R F
authors.initials: RF
authors.lastname: Kefford
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002455:Cell Division; D003593:Cytoplasm / Q000378:metabolism; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D010375:Pedigree; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D011506:Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53