Abstract |
There is increasing awareness of the role of mtDNA alterations in the development of cancer, as mtDNA point mutations are found at high frequency in a variety of human tumors. To determine the biological effects of mtDNA mutations in UV-induced skin tumors, hairless mice were irradiated to produce tumors, and the tumor mtDNAs were screened for single- nucleotide changes using temperature gradient capillary electrophoresis (TGCE), followed by direct sequencing. A mutation hot spot (9821insA) in the mitochondrially encoded tRNA arginine (mt-Tr) locus ( tRNA(Arg)) was discovered in approximately one-third of premalignant and malignant skin tumors. To determine the functional relevance of this particular mutation in vitro, cybrid cell lines containing different mt-Tr ( tRNA(Arg)) alleles were generated. The resulting cybrid cell lines contained the same nuclear genotype and differed only in their mtDNAs. The biochemical analysis of the cybrids revealed that the mutant haplotype is associated with diminished levels of complex I protein (CI), resulting in lower levels of baseline oxygen consumption and lower cellular adenosine triphosphate ( ATP) production. We hypothesize that this specific mtDNA mutation alters cellular biochemistry, supporting the development of keratinocyte neoplasia.
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Authors | Jana Jandova, Alex Eshaghian, Mingjian Shi, Meiling Li, Lloyd E King, Jaroslav Janda, James E Sligh |
Journal | The Journal of investigative dermatology
(J Invest Dermatol)
Vol. 132
Issue 2
Pg. 421-8
(Feb 2012)
ISSN: 1523-1747 [Electronic] United States |
PMID | 22011905
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
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Chemical References |
- DNA, Mitochondrial
- RNA, Transfer, Arg
- Adenosine Triphosphate
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Topics |
- Adenosine Triphosphate
(biosynthesis)
- Animals
- DNA, Mitochondrial
(genetics)
- Female
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Inbred C57BL
- Mutation
- Neoplasms, Radiation-Induced
(genetics, metabolism)
- Oxygen Consumption
- RNA, Transfer, Arg
(chemistry, genetics)
- Skin Neoplasms
(genetics, metabolism)
- Ultraviolet Rays
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