Elevated expression of DNA polymerase kappa in human lung cancer is associated with p53 inactivation: Negative regulation of POLK promoter activity by p53.
DNA polymerase kappa (POLkappa) is a low fidelity translesional DNA polymerase implicated in spontaneous and DNA damage-induced mutagenesis. We have previously shown that POLkappa was frequently overexpressed in human lung cancer tissues as compared with their matched non-tumorous tissue counterpart. In the present study, we found a close correlation between elevated POLkappa expression and p53 inactivation in lung cancer tissues. To investigate whether POLK expression might be regulated by p53, we have determined the transcriptional initiation site of POLK gene and examined its promoter activity in A549, H358-129, and PC-3 human lung cancer cell lines. Wild-type p53, but not a mutant p53 (R273H) devoid of the DNA-binding activity, strongly inhibited POLK promoter activity in these cells. In addition, POLK promoter exhibited a significantly higher activity in p53-/- murine embryo fibroblasts (MEF) than in p53+/- and p53+/+ MEF. These results link p53 status with POLkappa expression and suggest that loss of p53 function may in part contribute to the observed POLkappa upregulation in human lung cancers.
Wang
Yanqing
Y
Division of Pathology, Chiba Cancer Center Research Institute, Chiba 260-8717, Japan.
Seimiya
Mika
M
Kawamura
Kiyoko
K
Yu
Ling
L
Ogi
Tomoo
T
Takenaga
Keizo
K
Shishikura
Tomotane
T
Nakagawara
Akira
A
Sakiyama
Shigeru
S
Tagawa
Masatoshi
M
O-Wang
Jiyang
J
D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D005347:Fibroblasts / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000601:surgery; D051379:Mice; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000037:antagonists & inhibitors / Q000502:physiology*; D000099270:Y-Family DNA Polymerases
D004259:DNA-Directed DNA Polymerase; D016159:Tumor Suppressor Protein p53; C404302:POLK protein, human; D000099270:Y-Family DNA Polymerases; C498613:Polk protein, mouse