Genetic alterations of RD(INK4/ARF) enhancer in human cancer cells.
Recent identification of an enhancer element, RD(INK4/ARF) (RD), in the prominent INK4/ARF locus provides a novel mechanism to simultaneously regulate the transcription of p15(INK4B) (p15), p14(ARF) , and p16(INK4A) (p16) tumor suppressor genes. While genetic inactivation of p15, p14(ARF) , and p16 in human tumors has been extensively studied, little is known about genetic alterations of RD and its impact on p15, p14(ARF) , and p16 in human cancer. The purpose of this study was to investigate the potential existence of genetic alterations of RD in human cancer cells. DNAs extracted from 17 different cancer cell lines and 31 primary pheochromocytoma tumors were analyzed for deletion and mutation of RD using real-time PCR and direct DNA sequencing. We found that RD was deleted in human cancer cell lines and pheochromocytoma tumors at frequencies of 41.2% (7/17) and 13.0% (4/31), respectively. While some of these RD deletion events occurred along with deletions of the entire INK4/ARF locus, other RD deletion events were independent of genetic alterations in p15, p14(ARF) , and p16. Furthermore, the status of RD was poorly associated with the expression of p15, p14(ARF) , and p16 in tested cancer cell lines and tumors. This study demonstrates for the first time that deletion of the RD enhancer is a prevalent event in human cancer cells. Its implication in carcinogenesis remains to be further explored.
Division of Environmental Health Sciences, College of Public Health, The Ohio State University, Columbus, Ohio; Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
Junan
J
Li
Thomas J
TJ
Knobloch
Ming J
MJ
Poi
Zhaoxia
Z
Zhang
Andrew T
AT
Davis
Peter
P
Muscarella
Christopher M
CM
Weghorst
D000310:Adrenal Gland Neoplasms / Q000235:genetics; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D019175:DNA Methylation; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D017353:Gene Deletion; D006801:Humans; D009369:Neoplasms / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D014407:Tumor Cells, Cultured; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF