Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.25.1 (proteasome)
 28,817 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using the fitness-based interferential genetics (FIG) approach in yeast, potential in vivo gene targets of the Rpd3 histone deacetylase were selected. In agreement with previous studies using different methods, three genes were found to be involved in the translational machinery (MRPL27, FHL1 and RDN1). Moreover, other selected genes are linked to cell-cycle control (CSE4, AMN1, VAC17 and GRR1). In addition to playing a crucial role in cell cycle progression to the S phase and participating in the G(2)-M transition, GRR1 has important functions related to nutrient import to the cell via the the derepression of hexose transporters and the induction of amino acid permeases. Consistent with this, FIG selection also retrieved: the PMA1 gene, encoding the plasma H(+)-membrane ATPase; FOL2 and FOL3, involved in folic acid biosynthesis; and UBR2, which indirectly downregulates the proteasome genes. Finally, the other selected genes, ISU1, involved in the biosynthesis of the iron-sulphur cluster in mitochondria, and the less well functionally defined BSC5 and YBR270c, may participate in the cell's antioxidant and stress defence. The genes emerging from this FIG selection thus appear to be part of the downstream molecular mechanisms of the TOR signalling pathway, accounting for its effects on cell proliferation and longevity. From our results on gene expression under conditions of RPD3 overexpression, and by comparison with the available pharmacogenomics studies, it is proposed that FIG could be an invaluable approach for contributing to our understanding of complex cell regulatory systems.
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PMID:Direct in vivo access to potential gene targets of the RPD3 histone deactylase using fitness-based interferential genetics. 1753 20

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy. We evaluated 121 HCM patients, devoid of a mutation in known disease genes. We identified three novel variants in FHL1 (c.134delA/K45Sfs, c.459C>A/C153X and c.827G>C/C276S). Whereas the c.459C>A variant was associated with muscle weakness in some patients, the c.134delA and c.827G>C variants were associated with isolated HCM. Gene transfer of the latter variants in C2C12 myoblasts and cardiac myocytes revealed reduced levels of FHL1 mutant proteins, which could be rescued by proteasome inhibition. Contractility measurements after adeno-associated virus transduction in rat-engineered heart tissue (EHT) showed: (i) higher and lower forces of contraction with K45Sfs and C276S, respectively, and (ii) prolonged contraction and relaxation with both mutants. All mutants except one activated the fetal hypertrophic gene program in EHT. In conclusion, this study provides evidence for FHL1 to be a novel gene for isolated HCM. These data, together with previous findings of proteasome impairment in HCM, suggest that FHL1 mutant proteins may act as poison peptides, leading to hypertrophy, diastolic dysfunction and/or altered contractility, all features of HCM.
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PMID:Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy. 2252 91