The genetics of the human mitochondria and their role in neoplastic transformation will be studied using cultured human cells. Two human cancer lines as well as selected normal fibroblasts and their SV40-transformed derivatives have been collected and appropriate nuclear and cytoplasmic markers introduced. These lines, which originated from a variety of different origins, are being screened for mitochondrial DNA (mtDNA)-sequence polymorphisms using restriction endonucleases and heteroduplex analysis and for mitochondrial polypeptide variants using various electrophoresis produces and monoclonal antibodies against the inner membrane proteins. The mtDNA-sequence polymorphisms will then be used to assign selectable and polymorphic markers to the mtDNA and nuclear DNA. MtDNA-coded variants will be used in a detailed molecular analysis of mitochondrial gene segregation, studies on nucleocytoplasmic interaction, and in the development of new mitochondrial gene transfer technologies using purified mitochondria and mtDNA. Finally, the available nuclear and cytoplasmic genetic markers together with new gene transfer and selection procedures will be used to test a genetic hypothesis of neoplastic transformation and to investigate the role of mitochondrial or other cytoplasmic genes in this process.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM033022-06S1
Application #
3282325
Study Section
Mammalian Genetics Study Section (MGN)
Project Start
1983-06-01
Project End
1989-11-30
Budget Start
1988-09-01
Budget End
1989-11-30
Support Year
6
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Schools of Medicine
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Wallace, D C (1991) Mitochondrial genes and neuromuscular disease. Res Publ Assoc Res Nerv Ment Dis 69:101-20
Li, K; Hodge, J A; Wallace, D C (1990) OXBOX, a positive transcriptional element of the heart-skeletal muscle ADP/ATP translocator gene. J Biol Chem 265:20585-8
Torroni, A; Stepien, G; Hodge, J A et al. (1990) Neoplastic transformation is associated with coordinate induction of nuclear and cytoplasmic oxidative phosphorylation genes. J Biol Chem 265:20589-93
Li, K; Warner, C K; Hodge, J A et al. (1989) A human muscle adenine nucleotide translocator gene has four exons, is located on chromosome 4, and is differentially expressed. J Biol Chem 264:13998-4004
Neckelmann, N; Warner, C K; Chung, A et al. (1989) The human ATP synthase beta subunit gene: sequence analysis, chromosome assignment, and differential expression. Genomics 5:829-43
Wallace, D C (1989) Mitochondrial DNA mutations and neuromuscular disease. Trends Genet 5:9-13
Shuster, R C; Rubenstein, A J; Wallace, D C (1988) Mitochondrial DNA in anucleate human blood cells. Biochem Biophys Res Commun 155:1360-5
Santachiara Benerecetti, A S; Scozzari, R; Semino, O et al. (1988) Mitochondrial DNA polymorphisms in Italy. II. Molecular analysis of new and rare morphs from Sardinia and Rome. Ann Hum Genet 52:39-56
Wallace, D C; Ye, J H; Neckelmann, S N et al. (1987) Sequence analysis of cDNAs for the human and bovine ATP synthase beta subunit: mitochondrial DNA genes sustain seventeen times more mutations. Curr Genet 12:81-90
Neckelmann, N; Li, K; Wade, R P et al. (1987) cDNA sequence of a human skeletal muscle ADP/ATP translocator: lack of a leader peptide, divergence from a fibroblast translocator cDNA, and coevolution with mitochondrial DNA genes. Proc Natl Acad Sci U S A 84:7580-4

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