A melanoma-predisposing germline CDKN2A mutation with functional significance for both p16 and p14ARF.
The CDKN2A locus on human chromosome 9p21 encodes two proteins, p16 and p14ARF, that mainly regulate cell cycle progression and cell survival via the pRb and p53 pathways, respectively. Germline mutations in CDKN2A have been linked to development of cutaneous melanoma in some families with hereditary melanoma. Due to overlapping open reading frames in exon 2, some mutations in this exon affect both p16 and p14ARF. We previously reported a 24bp deletion in CDKN2A exon 2 in a patient with multiple primary melanomas and melanoma heredity. To further clarify the possible role of the 24bp deletion for melanoma development, especially with respect to p14ARF, we have studied the cellular distribution and function of the resulting p14ARF del (77-84) and p16 del (62-69) mutant proteins. We found that p14ARF del (77-84) had decreased nucleolar localization, and was less efficient than wt p14ARF in stabilizing p53, inducing G1 cell cycle arrest, and inhibiting colony formation. The p16 del (62-69) mutant localized predominantly to the cytoplasm, did not induce G1 cell cycle arrest, and failed to suppress colony formation. We conclude that p14ARF del (77-84) has retained the ability to stabilize MDM2 and p53, but that it is less potent than wt p14ARF. This partial functional defect may complement the clearly defective p16 del (62-69) mutant and thus contribute to melanoma development in patients carrying the 24bp deletion in CDKN2A.
Hashemi
Jamileh
J
Department of Oncology-Pathology, Research Laboratory of Radiumhemmet, Cancer Center Karolinska, R8:03, Karolinska Hospital, S-171 76 Stockholm, Sweden.
Lindström
Mikael S
MS
Asker
Charlotte
C
Platz
Anton
A
Hansson
Johan
J
Wiman
Klas G
KG
D000595:Amino Acid Sequence; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis / Q000502:physiology*; D016193:G1 Phase; D019942:Genes, p16; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000209:etiology / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000032:analysis; D051736:Proto-Oncogene Proteins c-mdm2; D025803:Tumor Suppressor Protein p14ARF / Q000032:analysis / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
D019941:Cyclin-Dependent Kinase Inhibitor p16; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2