ABSTRACT
Reduced DNA repair has been linked to an increased risk of cutaneous malignant melanoma, but insights into the molecular mechanisms of that link are scarce. The INK4a/ARF (CDKN2a) locus, which codes for the p16(INK4a) and p19ARF proteins, is often mutated in sporadic and familial malignant melanoma, but it has not been directly associated with reduced DNA repair. We transfected unirradiated mouse fibroblast cells with UV-treated DNA to measure DNA repair in normal, p16INK4a mutant, p19ARF mutant, or double mutant mouse host cells. Loss of either p16(INK4a) or p19ARF reduced the ability of the cells to process UV-induced DNA damage, independent of cell cycle effects incurred by the loss. These results may further explain why INK4a/ARF mutations predispose to malignant melanoma, a UV-induced tumor.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p16/genetics , Genes, p16/radiation effects , Melanoma/genetics , Mutation , Skin Neoplasms/genetics , Tumor Suppressor Protein p14ARF/genetics , Animals , Cyclin-Dependent Kinase Inhibitor p16/radiation effects , DNA Damage/radiation effects , DNA Repair/radiation effects , Fibroblasts/metabolism , Fibroblasts/radiation effects , Melanoma/etiology , Melanoma/metabolism , Mice , Skin Neoplasms/etiology , Skin Neoplasms/metabolism , Transfection , Tumor Suppressor Protein p14ARF/radiation effects , Ultraviolet RaysABSTRACT
Previous studies have shown that during the period subsequent to the Chernobyl accident, increases in morbidity, aggressivity and proliferative activity of renal-cell carcinomas (RCCs) in Ukrainian patients were recognized. The present paper describes the molecular alterations of those tumor suppressor genes located on chromosome 9p21 ( INK4a/ARF locus and p15(INK4B)) in 26 primary renal-cell epithelial tumors from patients with different degrees of radiation exposure after the Chernobyl accident in Ukraine. Radiometric measurement of Cesium 137 ((137)Cs) was conducted with 1-day urine from all patients before surgery. Our results demonstrate that RCCs from patients living in the radio-contaminated areas showed aberrant hypermethylation of p14(ARF) and p16(INK4A) genes, associated with increased p38MAPK, p14(ARF), mdm2, cyclinD1 and Ki67 protein expression levels. Present findings show the possibility that chronic long-term low-dose radiation activates the INK4a/ARF locus, targeted by activation of the p38MAPK cascade. These actions could lead to disruptions and loss of cell cycle checkpoints and, thereby, to cellular transformation.
Subject(s)
Carcinoma, Renal Cell/genetics , Cell Cycle/radiation effects , Genes, p16/radiation effects , Kidney Neoplasms/genetics , Neoplasms, Radiation-Induced/genetics , Adult , Aged , Carcinoma, Renal Cell/metabolism , Carcinoma, Renal Cell/pathology , Cell Cycle/genetics , Cesium Isotopes/urine , Cyclin-Dependent Kinase Inhibitor p16/genetics , Cyclin-Dependent Kinase Inhibitor p16/radiation effects , DNA Methylation , Female , Humans , Immunohistochemistry , Kidney Neoplasms/metabolism , Kidney Neoplasms/pathology , Male , Middle Aged , Mutation , Neoplasms, Radiation-Induced/pathology , Polymerase Chain Reaction , Tumor Suppressor Protein p14ARF/genetics , Tumor Suppressor Protein p14ARF/radiation effects , Ukraine , p38 Mitogen-Activated Protein Kinases/metabolismABSTRACT
Inactivation of the INK4a/ARF (or CDKN2a) locus is a common and critical genetic event in the development of human and mouse melanoma. This locus engages the Rb and p53 tumor suppressor pathways through its capacity to encode two distinct gene products, p16(INK4a) and p14(ARF). This review highlights the body of evidence supporting a role for both p16(INK4a) and p14(ARF) in the suppression of melanoma, and speculates as to why this locus is preferentially targeted in this tumor type. In addition, the potential importance of these two pathways in mediating UV-induced melanoma genesis will be addressed via genetic and molecular evidence in the mouse.
