The INK4a /ARF locus: role in cell cycle control for renal cell epithelial tumor growth after the Chernobyl accident.
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.
Romanenko
Alina
A
Department of Pathology, Institute of Urology, Academy of Medical Sciences of Ukraine, 9(a) Yu. Kotzubinsky, 04053 Kiev, Ukraine.
Morell-Quadreny
Luisa
L
Lopez-Guerrero
Jose Antonio
JA
Pellin
Antonio
A
Nepomnyaschy
Valentin
V
Vozianov
Alexander
A
Llombart-Bosch
Antonio
A
D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics / Q000528:radiation effects*; D002587:Cesium Isotopes / Q000652:urine; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000528:radiation effects; D019175:DNA Methylation; D005260:Female; D019942:Genes, p16 / Q000528:radiation effects*; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009381:Neoplasms, Radiation-Induced / Q000235:genetics* / Q000473:pathology; D016133:Polymerase Chain Reaction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000528:radiation effects; D014455:Ukraine; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D002587:Cesium Isotopes; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D048051:p38 Mitogen-Activated Protein Kinases