Mutations in the INK4a/ARF melanoma susceptibility locus functionally impair p14ARF.
The INK4a/ARF locus encodes two cell cycle regulatory proteins, the cyclin-dependent kinase inhibitor, p16(INK4a), and the p53 activator, p14(ARF). Germline mutations in this locus are associated with melanoma susceptibility in 20-40% of multiple case melanoma families. Many of these mutations specifically impair p16(INK4a), whereas mutations uniquely targeting p14(ARF) are rare. Nevertheless, the importance of p14(ARF) has not been excluded because more than 40% of INK4a/ARF alterations affect p16(INK4a) and p14(ARF). We now report that p14(ARF) is functionally impaired in melanoma kindreds carrying INK4a/ARF mutations. Of the seven INK4a/ARF mutations tested, three altered the subcellular distribution of p14(ARF) and diminished the ability of p14(ARF) to activate the p53 pathway. This work establishes the importance of p14(ARF) in melanoma predisposition.
Rizos
H
H
Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales 2145, Australia. helen_rizos@wmi.usyd.edu.au
Darmanian
A P
AP
Holland
E A
EA
Mann
G J
GJ
Kefford
R F
RF
D000595:Amino Acid Sequence; D001483:Base Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D004273:DNA, Neoplasm; D019084:Fluorescent Antibody Technique, Indirect; D020022:Genetic Predisposition to Disease; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53