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Tfam  -  transcription factor A, mitochondrial

Mus musculus

Synonyms: AI661103, Hmgts, TS-HMG, Testis-specific high mobility group protein, Transcription factor A, mitochondrial, ...
 
 
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Disease relevance of Tfam

 

High impact information on Tfam

 

Biological context of Tfam

  • Apoptosis was studied in embryos with homozygous disruption of the mitochondrial transcription factor A gene (Tfam) and tissue-specific Tfam knockout animals with severe respiratory chain deficiency in the heart [5].
  • The tissue-specific mitochondrial transcription factor A (Tfam) knockout mice of this study displayed a progressive heart phenotype with depletion of mtDNA and an accompanying severe decline of respiratory chain enzyme activities along with a decreased mitochondrial ATP production rate [6].
  • The introduced human TFAM gene was regulated in a similar fashion as the endogenous mouse Tfam gene and expression of the human TFAM protein in the mouse did not result in down-regulation of the endogenous expression [7].
  • The gene for the SR Ca(2+) binding protein calsequestrin-2 (CASQ2), as well as other genes encoding proteins involved in SR Ca(2+) handling, showed decreased expression in Tfam knockout hearts [2].
  • The comparison with other available Tfam sequences from mammals has revealed a high degree of conservation (above 90%) both in CDS and introns [8].
 

Anatomical context of Tfam

  • Conditional inactivation of the nDNA mitochondrial transcription factor (Tfam) gene in the heart resulted in neonatal lethal cardiomyopathy, while its inactivation in the pancreatic beta-cells caused diabetes [9].
  • We have found increased cell death or apoptosis induction in both germ line and tissue-specific Tfam knockouts [10].
  • An evolutionary analysis of HMG boxes indicates that the delta HMG boxes are similar to the HMG boxes of tsHMG, a protein that appears in elongating mouse spermatids when they condense and cease transcription, suggesting that delta could play a similar role in the micronucleus [11].
  • We also show that the tsHMG protein is the substrate of a Ca2+-phospholipid-dependent protein kinase (protein kinase C) present in testis extracts of adult mice and demonstrate that phosphorylation by protein kinase C is required for both the DNA-binding and the topoisomerase I-dependent supercoiling activities of tsHMG [12].
  • To test this possibility, a human cervical carcinoma cell line (HeLa) was constructed which ectopically expressed tsHMG under the control of an inducible promoter [13].
 

Associations of Tfam with chemical compounds

  • In line with this, application of the beta-adrenergic agonist isoproterenol resulted in frequent doublet Ca(2+) transients in Tfam knockout cardiomyocytes [2].
  • The binding affinity and specificity of tsHMG for cisplatin-modified DNA are exceptional compared to those of other HMG-domain proteins studied previously [14].
 

Other interactions of Tfam

  • We report here that hallmarks of mtDNA mutation disorders can be reproduced in the mouse using a conditional mutation strategy to manipulate the expression of the gene encoding mitochondrial transcription factor A (Tfam, previously named mtTFA), which regulates transcription and replication of mtDNA [4].

References

  1. Increased mitochondrial mass in mitochondrial myopathy mice. Wredenberg, A., Wibom, R., Wilhelmsson, H., Graff, C., Wiener, H.H., Burden, S.J., Oldfors, A., Westerblad, H., Larsson, N.G. Proc. Natl. Acad. Sci. U.S.A. (2002) [Pubmed]
  2. Abnormal Ca(2+) release and catecholamine-induced arrhythmias in mitochondrial cardiomyopathy. Tavi, P., Hansson, A., Zhang, S.J., Larsson, N.G., Westerblad, H. Hum. Mol. Genet. (2005) [Pubmed]
  3. Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes. Silva, J.P., Köhler, M., Graff, C., Oldfors, A., Magnuson, M.A., Berggren, P.O., Larsson, N.G. Nat. Genet. (2000) [Pubmed]
  4. Dilated cardiomyopathy and atrioventricular conduction blocks induced by heart-specific inactivation of mitochondrial DNA gene expression. Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J.C., Kahn, C.R., Clayton, D.A., Barsh, G.S., Thorén, P., Larsson, N.G. Nat. Genet. (1999) [Pubmed]
  5. Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Wang, J., Silva, J.P., Gustafsson, C.M., Rustin, P., Larsson, N.G. Proc. Natl. Acad. Sci. U.S.A. (2001) [Pubmed]
  6. A switch in metabolism precedes increased mitochondrial biogenesis in respiratory chain-deficient mouse hearts. Hansson, A., Hance, N., Dufour, E., Rantanen, A., Hultenby, K., Clayton, D.A., Wibom, R., Larsson, N.G. Proc. Natl. Acad. Sci. U.S.A. (2004) [Pubmed]
  7. Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Ekstrand, M.I., Falkenberg, M., Rantanen, A., Park, C.B., Gaspari, M., Hultenby, K., Rustin, P., Gustafsson, C.M., Larsson, N.G. Hum. Mol. Genet. (2004) [Pubmed]
  8. Study of the mitochondrial transcription factor A (Tfam) gene in the primate Presbytis cristata. D'Errico, I., Reyes, A., Dinardo, M.M., Gadaleta, G. Gene (2005) [Pubmed]
  9. Mouse models for mitochondrial disease. Wallace, D.C. Am. J. Med. Genet. (2001) [Pubmed]
  10. Manipulation of mitochondrial DNA gene expression in the mouse. Silva, J.P., Larsson, N.G. Biochim. Biophys. Acta (2002) [Pubmed]
  11. Four distinct and unusual linker proteins in a mitotically dividing nucleus are derived from a 71-kilodalton polyprotein, lack p34cdc2 sites, and contain protein kinase A sites. Wu, M., Allis, C.D., Sweet, M.T., Cook, R.G., Thatcher, T.H., Gorovsky, M.A. Mol. Cell. Biol. (1994) [Pubmed]
  12. The testis-specific high-mobility-group protein, a phosphorylation-dependent DNA-packaging factor of elongating and condensing spermatids. Alami-Ouahabi, N., Veilleux, S., Meistrich, M.L., Boissonneault, G. Mol. Cell. Biol. (1996) [Pubmed]
  13. Testis-specific HMG-domain protein alters the responses of cells to cisplatin. Zamble, D.B., Mikata, Y., Eng, C.H., Sandman, K.E., Lippard, S.J. J. Inorg. Biochem. (2002) [Pubmed]
  14. Binding of tsHMG, a mouse testis-specific HMG-domain protein, to cisplatin-DNA adducts. Ohndorf, U.M., Whitehead, J.P., Raju, N.L., Lippard, S.J. Biochemistry (1997) [Pubmed]
 
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