Mitochondrial impairment in p53-deficient human cancer cells.
The mechanism linking p53 inactivation to human cell malignancy remains unclear. Studies have indicated that mitochondrial dysfunction is involved in carcinogenesis. In this study we investigated the role of p53 in mitochondrial DNA (mtDNA) mutation and maintenance of proper mitochondrial function. We measured mtDNA mutation and found no difference in frequency of mutation between the p53(+/+) and p53(-/-) cell lines. However, mitochondrial cytochrome c oxidase (COX) activity was significantly diminished in p53(-/-) cells. This decrease in COX activity was attributed to decreased protein levels of the COXII subunit encoded by the mitochondrial genome and was not due to mutation in the mitochondrial COXII gene. Further investigation revealed no concomitant decrease in COXII mRNA levels in p53(-/-) cells and the stability of mRNA in p53(-/-) cells was unaffected. This study suggests that decreased COX activity is likely due to post-transcriptional regulation of the COXII subunit by p53. COX is a critical enzyme in the mitochondrial electron transport chain and reduced COX activity may affect mitochondrial structure. However, examination of mitochondrial ultrastructure revealed no obvious differences between p53(+/+) and p53(-/-) cell lines. Together, our study suggests that p53 is involved in regulation of COXII at the protein level but not at the mRNA level. p53 does not affect mtDNA mutation or mitochondrial ultrastructure.
Zhou
Shaoyu
S
Sidney Kimmel Cancer Center, Johns Hopkins School of Medicine, Bunting-Blaustein Cancer Research Building, 1650 Orleans Street, Room 143, Baltimore, MD 21231, USA.
Kachhap
Sushant
S
Singh
Keshav K
KK
D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins; D008854:Microscopy, Electron; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency*
D004272:DNA, Mitochondrial; D007527:Isoenzymes; D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D003576:Electron Transport Complex IV