Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory complexes III, IV and V are formed by components of both nuclear and mitochondrial origin and are embedded in the inner mitochondrial membrane. Their assembly requires the auxiliary factor Oxa1, and the absence of this protein has severe consequences on these three major respiratory chain enzymes. We have studied, in the yeast Saccharomyces cerevisiae, the effect of the loss of Oxa1 function and of other respiratory defects on the expression of nuclear genes encoding components of the respiratory complexes and tricarboxylic acid cycle enzymes. We observed that the concomitant decrease in the level of two respiratory enzymes, complexes III and IV, led to their repression. These genes are known targets of the transcriptional activator complex Hap2/3/4/5 that plays a central role in the reprogramming of yeast metabolism when cells switch from a fermenting, glucose-repressed state to a respiring, derepressed state. We found that the Hap4 protein, the regulatory subunit of the transcriptional complex, was present at a lower level in the oxa1 mutants whereas no change in HAP4 transcript level was observed, suggesting a posttranscriptional modulation. In addition, an altered mitochondrial morphology was observed in mutants with decreased expression of Hap2/3/4/5 target genes. We suggest that the aberrant mitochondrial morphology, presumably caused by the severely decreased level of at least two respiratory enzymes, might be part of the signalling pathway linking the mitochondrial defect and Hap2/3/4/5.
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PMID:Multiple defects in the respiratory chain lead to the repression of genes encoding components of the respiratory chain and TCA cycle enzymes. 1924 17

Alterations in mitochondrial metabolism have been associated with age-related neurodegenerative disorders. This is seen in diseases caused by misfolding of proteins with expanded polyglutamine (polyQ) tracts, such as Huntington's disease. Although evidence of mitochondrial impairment has been extensively documented in patients and disease models, the mechanisms involved and their relevance to the initiation of polyQ cytotoxicity and development of clinical manifestations remain controversial. We report that in yeast models of polyQ cytotoxicity, wild-type and mutant polyQ domains might associate early with the outer mitochondrial membrane. The association of mutant domains with mitochondrial membranes could contribute to induce significant changes in mitochondrial physiology, ultimately compromising the cell's ability to respire. The respiratory defect can be fully prevented by enhancing mitochondrial biogenesis by overexpression of Hap4p, the catalytic subunit of the transcriptional activator Hap2/3/4/5p complex, the master regulator of the expression of many nuclear genes encoding mitochondrial proteins in yeast. Protecting cellular respiratory capacity in this way ameliorates the effect of expanded polyQ on cellular fitness. We conclude that mitochondrial dysfunction is an important contributor to polyQ cytotoxicity. Our results suggest that therapeutic approaches enhancing mitochondrial biogenesis could reduce polyQ toxicity and delay the development of clinical symptoms in patients.
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PMID:Suppression of polyglutamine-induced cytotoxicity in Saccharomyces cerevisiae by enhancement of mitochondrial biogenesis. 2000 43

Promoter activation drives gene transcriptional output. Here we report generating site-specifically integrated single-copy promoter transgenes and measuring their expression to indicate promoter activities at single-mRNA level. mRNA counts, Pol II density and Pol II firing rates of the Ccnb1 promoter transgene resembled those of the native Ccnb1 gene both among asynchronous cells and during the cell cycle. We observed distinct activation states of the Ccnb1 promoter among G1 and G2/M cells, suggesting cell cycle-independent origin of cell-to-cell variation in Ccnb1 promoter activation. Expressing a dominant-negative mutant of NF-YA, a key transcriptional activator of the Ccnb1 promoter, increased its "OFF"/"ON" time ratios but did not alter Pol II firing rates during the "ON" period. Furthermore, comparing H3K4me2 and H3K79me2 levels at the Ccnb1 promoter transgene and the native Ccnb1 gene indicated that the enrichment of these two active histone marks did not predispose higher transcriptional activities. In summary, this experimental system enables bridging transcription imaging with molecular analysis to provide novel insights into eukaryotic transcriptional regulation.
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PMID:Single-cell, single-mRNA analysis of Ccnb1 promoter regulation. 2852


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