Overexpression of a fish CDKN2 gene in a hereditary melanoma model

• Published in: Carcinogenesis (New York) Vol. 21; no. 4; pp. 599 - 605
• Main Authors: Kazianis, Steven, Coletta, Luis Della, Morizot, Donald C., Johnston, Dennis A., Osterndorff, Elizabeth A., Nairn, Rodney S.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.04.2000; Oxford Publishing Limited (England)
• Subjects: Animal tumors. Experimental tumors; Animals; Biological and medical sciences; CDKN2A gene; CDKN2B gene; CDKN2X gene; CpG Islands; Cyclin-Dependent Kinase Inhibitor p16 - genetics; Cyprinodontiformes; DNA Methylation; Female; Fish Diseases - genetics; Genes, Tumor Suppressor; INK4A gene; Medical sciences; Melanoma - genetics; Melanoma - veterinary; MTS1 gene; P16 gene; Promoter Regions, Genetic; RNA - analysis; Spontaneous animal tumors; Tumors; Xiphophorus; Xmrk-2 gene; Animal model; Skin disease; Enzyme; Transcription promoter; Transferases; Spontaneous; Enzyme inhibitor; Gene overexpression; Malignant tumor; Gene expression; Hereditary; Carcinogenesis; CDKN2 gene; Vertebrata; Protein kinase; Animal; DNA; Pisces; Malignant melanoma; Cytosine; Methylation; Tumor suppressor gene; Phenotypic hybrid
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/21.4.599

The fish genus Xiphophorus provides a vertebrate model useful in etiological studies of cancer. Hybrid fish can spontaneously develop melanomas deriving from the inheritance of melanistic pigment patterns and the simultaneous absence of proper genetic regulation. A cyclin-dependent kinase inhibitor gene, termed CDKN2X, was mapped to a genomic region that is implicated in fish melanoma tumor suppression. The related human tumor suppressor locus CDKN2A (P16, INK4A, MTS1) is deleted, mutated or transcriptionally repressed through methylation of cytosine bases within the 5′ CpG island in a variety of neoplasms, including melanoma. The fish CDKN2X locus harbors a CpG island within its promoter and first exon, analogous in location to CpG islands in human CDKN2A and CDKN2B loci. The methylation state of individual CpG dinucleotides was investigated in genomic DNA derived from control tissues and melanomas within the CDKN2X 5′ CpG island. The studied genomic area was found to be virtually unmethylated in all tested tissues including melanomas. In addition, RNA expression studies of the fish CDKN2X locus revealed that it is significantly overexpressed in melanoma, in contrast to what has been reported for the human CDKN2A locus in melanoma. Such overexpression may be a consequence of the pronounced upregulation of the Xmrk-2 receptor tyrosine kinase oncogene reported in several Xiphophorus melanoma models.