title: Novel frameshift mutation in the p16/INK4A tumor suppressor gene in canine breast cancer alters expression from the p16/INK4A/p14ARF locus.
abstract: The INK4 family of cyclin-dependent kinase inhibitors (CKI) encode important cell cycle regulators that tightly control cell cycle during G1 to S phase. These related genes are considered tumor suppressors as loss of function contributes to the malignant phenotype. Expression of CKIs p16, p14ARF, or p15 were defective in six different canine mammary tumor (CMT) cell lines compared to normal thoracic canine fibroblasts. This suggests CKI defects are frequently responsible for neoplastic transformation in canine mammary carcinomas. p16 and p14ARF are two alternatively spliced products derived from the canine p16/INK4A/p14ARF gene locus. Despite omissions in the published p16 transcript and canine genome and the presence of GC-rich repeats, we determined the complete coding sequence of canine p16 revealing a deletion and frameshift mutation in p16 exon 1α in CMT28 cells. In addition, we determined canine p14ARF mRNA and protein sequences. Mapping of these mutations uncovered important aspects of p16 and p14ARF expression and defects in CMT28 cells shifting the p16 reading frame into p14ARF making a fusion protein that was predicted to be truncated, unstable and devoid of structural and functional integrity. This data describes an important neoplastic mechanism in the p16/INK4A/p14ARF locus in a spontaneous canine model of breast cancer.
authors: Department of Pathobiology, AURIC-Auburn University Research Initiative in Cancer, College of Veterinary Medicine Auburn University, Auburn, AL 36849, USA.
authors: Farruk M
authors: FM
authors: Lutful Kabir
authors: Payal
authors: P
authors: Agarwal
authors: Patricia
authors: P
authors: Deinnocentes
authors: Jishan
authors: J
authors: Zaman
authors: Allison Church
authors: AC
authors: Bird
authors: R Curtis
authors: RC
authors: Bird
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics* / Q000378:metabolism; D004285:Dogs; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D019942:Genes, p16; D056426:Genetic Loci; D006801:Humans; D008321:Mammary Glands, Animal / Q000378:metabolism / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D016366:Open Reading Frames; D017386:Sequence Homology, Amino Acid; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000378:metabolism
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D015514:Oncogene Proteins, Fusion; D025803:Tumor Suppressor Protein p14ARF