PHYSIOLOGICAL REGULATORS OF CYTOCHROME OXIDASE GENES

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DESCRIPTION: A number of neural, muscular and retinal degenerative diseases with wide ranging pathological conditions are associated with inherited or somatic mutations targeted to the mitochondrial electron transport chain characterization of COX from different mammalian tissues showed a predictable change in the catalytic levels of ubiquitous, but variably expressed COX Vb subunit varied in different tissues and under hypoxic conditions. Results also suggest the involvement of a multi-factor binding negative enhancer in the tissue dependent variations of COX Bv expression and also in the transcription down regulation of the gene under hypoxic conditions. Additionally, the investigators have characterized a novel bHLH factor in the cardiac muscle specific transcription activation of the muscle specific COX VIII (H) gene. Based on this, it is proposed to continue studies on the biochemical characterization of the COX complex and transcription regulation of COX genes under different physiological conditions as follows: 1) Further characterization of the COX Bv negative enhancer with a view to understand how the activity of this negative enhancer is modulated in different tissues and during myogenesis. Protein factors binding to the individual motifs (including the YY-1', GTG motifs) will be purified and the mode of intermolecular interaction between proteins binding to four individual DNA motifs of this region will be studied. 2) Mechanisms of hypoxia-induced down regulation of nuclear encoded COX Bv and MtTFA mRNAs, and upregulation of COX VIII (H) mRNA in C2C12 cells will be investigated to elucidate the nature of cis-acting DNA elements and the protein factors mediating these cell specific effects. 3) Purification and characterization of the cardiac muscle specific bHLH protein factor will be continued using DNA affinity chromatography and the Yeast two-hybrid selection system.