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Query: UNIPROT:P06889 (Mol)
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Many introns in Drosophila and other invertebrates are less than 80 nucleotides in length, too small to be recognized by the vertebrate splicing machinery. Comparison of nuclear splicing extracts from human HeLa and Drosophila Kc cells has revealed species-specificity, consistent with the observed size differences. Here we present additional results with the 68 nucleotide fifth intron of the Drosophila myosin heavy chain gene. As observed with the 74 nucleotide second intron of the Drosophila white gene, the wild-type myosin intron is accurately spliced in a homologous extract, and increasing the size by 16 nucleotides both eliminates splicing in the Drosophila extract and allows accurate splicing in the human extract. In contrast to previous results, however, an upstream cryptic 5' splice site is activated when the wild-type myosin intron is tested in a human HeLa cell nuclear extract, resulting in the removal of a 98 nucleotide intron. The size dependence of splicing in Drosophila extracts is also intron-specific; we noted that a naturally larger (150 nucleotide) intron from the ftz gene is efficiently spliced in Kc cell extracts that do not splice enlarged introns (of 84, 90, 150 or 350 nucleotides) derived from the 74 nucleotide white intron. Here, we have exploited that observation, using a series of hybrid introns to show that a region of 46 nucleotides at the 3' end of the white intron is sufficient to confer the species-specific size effect. At least two sequence elements within this region, yet distinct from previously described branchpoint and pyrimidine tract signals, are required for efficient splicing of small hybrid introns in vitro.
J Mol Biol 1995 Oct 27
PMID:Localization of sequences required for size-specific splicing of a small Drosophila intron in vitro. 747 25

The number of dihydropyridine and ryanodine receptors (DHP-R and RyR) has been measured in control and hypertrophied ventricles from rats, guinea pigs and ferrets to determine whether these two channels contribute to the alterations in excitation-contraction coupling (ECC), and in Ca2+ transient during compensated cardiac hypertrophy. We found that ventricular hypertrophy did not change the density of DHP-R. Mild hypertrophy did not alter the density of RyR in the rat but decreased it in the guinea-pig and in the ferret (30% and 36%, respectively). Severe hypertrophy decreased the density of RyR by 20% in the rat and by 34% in the guinea-pig. Therefore, the decrease is greater in ferret and guinea-pig hearts than in rat heart. We conclude that the sarcoplasmic reticulum (SR) Ca2+ release channels but not the L-type Ca2+ channels could contribute to the slowing of intracellular Ca2+ movements and to the reduced velocity of shortening of the hypertrophied hearts. We suggest that, in the guinea pig and ferret hearts which express only the beta myosin heavy chain (MHC) isoform, the reduced velocity of shortening during hypertrophy is related to the decrease in RyR density, whereas in the rat, it is regulated primarily via a shift in the MHC isoform, except in severe hypertrophy in which the moderate decrease in RyR would also be involved.
J Mol Cell Cardiol 1995 May
PMID:The effects of compensated cardiac hypertrophy on dihydropyridine and ryanodine receptors in rat, ferret and guinea-pig hearts. 747 81

We investigated the expression of myosin heavy chain (MHC) isoenzymes in embryonic rat ventricles cultured in the anterior eye chamber of an adult rat. In oculo, these grafts beat and mature in an environment where the hormonal milieu can be manipulated. S1 nuclease protection assays were performed on pooled samples of ventricle grafts and compared to normally growing ventricles. At the time of grafting (embryonic day 12, E-12), 23 +/- 4% of the MHC mRNA was of the alpha isoform. While the proportion of ventricular alpha-MHC mRNA did not increase in utero, embryonic ventricles cultured in oculo showed a rapid increase in the relative amount of alpha-MHC mRNA expression (to 84 +/- 10% by 3 days and 86 +/- 5% by 8 days in oculo). alpha-MHC mRNA expression predominated through 8 weeks of culture in oculo, being 76% at 8 weeks in oculo. Additional experiments were performed to determine whether the rapid conversion to alpha-MHC expression resulted from exposure to adult levels of testosterone or thyroid hormone. Reduction of testosterone exposure to nondetectable levels by host orchiectomy did not affect the rapid conversion to alpha-MHC mRNA expression. Exposure to a hypothyroid milieu (i.e., PTU-treated hosts) decreased but did not prevent the conversion from beta- to alpha-MHC mRNA expression at 8 days in oculo; with 83% of the MHC mRNA being of the alpha isoform in hypothyroid hosts compared to 95% in euthyroid hosts. After 8 weeks of culture in hypothyroid hosts, however, alpha-MHC mRNA expression was undetectable in grafted ventricles. These data suggest that E-12 myocardial grafts respond to the hormonal milieu of an adult rat with rapid conversion from beta- to alpha-MHC mRNA expression and that alpha-MHC expression in early developing heart may show reduced sensitivity to downward modulation by a hypothyroid hormonal milieu.
J Mol Cell Cardiol 1995 Jul
PMID:Rapid conversion from beta-MHC to alpha-MHC mRNA expression in embryonic rat ventricle cultured in oculo is not dependent on thyroid hormone or testosterone. 747 87

Imprecise excision of the Caenorhabditis elegans transposon Tc1 from a specific site of insertion within the unc-54 myosin heavy chain gene generates either wild-type or partial phenotypic revertants. Wild-type revertants and one class of partial revertants contain insertions of four nucleotides in the unc-54 third exon (Tc1 "footprints"). Such revertants express large amounts of functional unc-54 myosin despite having what would appear to be frameshifting insertions in the unc-54 third exon. We demonstrate that these Tc1 footprints act as efficient 5' splice sites for removal of the unc-54 third intron. Splicing of these new 5' splice sites to the normal third intron splice acceptor removes the Tc1 footprint from the mature mRNA and restores the normal translational reading frame. Partial revertant unc-54(r661), which contains a single nucleotide substitution relative to the wild-type gene, is spliced similarly, except that the use of its new 5' splice site creates a frameshift in the mature mRNA rather than removing one. In all of these revertants, two alternative 5' splice sites are available to remove intron 3. We determined the relative efficiency with which each alternative 5' splice site is used by stabilizing frameshifted mRNAs with smg(-) genetic backgrounds. In all cases, the upstream member of the two alternative sites is used preferentially (> 75% utilization). This may reflect an inherent preference of the splicing machinery for the upstream member of two closely spaced 5' splice sites. Creation of new 5' splice sites may be a general characteristic of Tc1 insertion and excision events.
Mol Cell Biol 1994 May
PMID:Imprecise excision of the Caenorhabditis elegans transposon Tc1 creates functional 5' splice sites. 751 51

In order to perform comparative studies of the cardiac myosin heavy chain (MyHC) genes, we determined the sequence of the Syrian hamster beta-MyHC gene and its 5' flanking region. This 33,960 basepair (bp) sequence contains 12,196 bp of the 5' flanking region as well as 21,731 bp of the complete beta-MyHC gene, with its 3' end overlapping with the alpha-MyHC gene. All the exon/intron boundaries were determined and relative to the human beta-MyHC gene, an extra 5' untranslated exon was identified. The isolation and sequencing of the Syrian hamster beta-MyHC gene may further the understanding about the regulation and the evolution of the cardiac MyHC genes.
J Mol Cell Cardiol 1995 Apr
PMID:Characterization and structural organization of the cardiac beta-myosin heavy chain gene from Syrian hamster. 756 4

MRF4, MyoD, myogenin, and Myf-5 are muscle-specific basic helix-loop-helix transcription factors that share the ability to activate the expression of skeletal muscle genes such as those encoding alpha-actin, myosin heavy chain, and the acetylcholine receptor subunits. The muscle regulatory factors (MRFs) also exhibit the unique capacity to initiate the myogenic program when ectopically expressed in a variety of nonmuscle cell types, most notably C3H10T1/2 fibroblasts (10T1/2 cells). The commitment of myoblasts to terminal differentiation, although positively regulated by the MRFs, also is controlled negatively by a variety of agents, including several growth factors and oncoproteins such as fibroblast growth factor (FGF-2), transforming growth factor beta 1 (TGF-beta 1), and Ras p21Val. The molecular mechanisms by which these varied agents alter myogenic terminal differentiation events remain unclear. In an effort to establish whether Ras p21Val represses MRF activity by directly targeting the MRF proteins, we examined the DNA binding and transcription activation potentials of MRF4 and MyoD when expressed in 10T1/2 cells or in 10T1/2 cells expressing Ras p21Val. Our results demonstrate that Ras p21Val inhibits terminal differentiation events by targeting the basic domain of the MRFs, and yet the mechanism underlying this inhibition does not involve altering the DNA binding or the inherent transcriptional activity of these regulatory factors. In contrast, FGF-2 and TGF-beta 1 block terminal differentiation by repressing the transcriptional activity of the MRFs. We conclude that the Ras p21Val block in differentiation operates via an intracellular signaling pathway that is distinct from the FGF-2 and TGF-beta 1 pathways.
Mol Cell Biol 1995 Oct
PMID:Ras p21Val inhibits myogenesis without altering the DNA binding or transcriptional activities of the myogenic basic helix-loop-helix factors. 756 69

We have determined the molecular and ultrastructural defects associated with three homozygous-viable myosin heavy chain mutations of Drosophila melanogaster. These mutations cause a dominant flightless phenotype but allow relatively normal assembly of indirect flight muscle myofibrils. As adults age, the contents of the indirect flight muscle myofibers are pulled to one end of the thorax. This apparently results from myofibril "hyper-contraction", and leads to sarcomere rupture and random myofilament orientation. All three mutations cause single amino acid changes in the light meromyosin region of the myosin rod. Two change the same glutamic acid to a lysine residue and the third affects an amino acid five residues away, substituting histidine for arginine. Both affected residues are conserved in muscle myosins, cytoplasmic myosins and paramyosins. The mutations are associated with age-dependent, site-specific degradation of myosin heavy chain and failure to accumulate phosphorylated forms of flightin, an indirect flight muscle-specific protein previously localized to the thick filament. Given the repeating nature of the hydrophobic and charged amino acid residues of the myosin rod and the near-normal assembly of myofibrils in the indirect flight muscle of these mutants, it is remarkable that single amino acid changes in the rod cause such severe defects. It is also interesting that these severe defects are not apparent in other muscles. These phenomena likely arise from the highly organized nature and rigorous performance requirements of indirect flight muscle, and perhaps from the interaction of myosin with flightin, a protein specific to this muscle type.
J Mol Biol 1995 May 26
PMID:Defects in the Drosophila myosin rod permit sarcomere assembly but cause flight muscle degeneration. 777 66

In vertebrate striated muscle, troponin-tropomyosin is responsible, in part, not only for transducing the effect of calcium on contractile protein activation, but also for inhibiting actin and myosin interaction when calcium is absent. The regulatory troponin (Tn) complex displays several molecular and calcium binding variations in cardiac muscles of different species and undergoes genetic changes with development and in various pathologic states. Extensive reviews on the role of tropomyosin (Tm) and Tn in the regulation of striated muscle contraction have been published describing the molecular mechanisms involved in contractile protein regulation. In our studies, we have found an increase in Mg2+ ATPase activity in cardiac myofibrils from dystrophic hamsters and in rats with chronic coronary artery narrowing. The abnormalities in myofibrillar ATPase activity from cardiomyopathic hamsters were largely corrected by recombining the preparations with a TnTm complex isolated from normal hamsters indicating that the TnTm may play a major role in altered myocardial function. We have also observed down regulation of Ca2+ Mg2+ ATPase of myofibrils from hypertrophic guinea pig hearts, myocardial infarcted rats and diabetic-hypertensive rat hearts. In myosin from diabetic rats, this abnormality was substantially corrected by adding troponin-tropomyosin complex from control hearts. All of these disease models are associated with decreased ATPase activities of pure myosin and in the case of rat and hamster models, shifts of myosin heavy chain from alpha to beta predominate. In summary, there are three main troponin subunit components which might alter myofibrillar function however, very few direct links of molecular alterations in the regulatory proteins to physiologic and pathologic function have been demonstrated so far.
Mol Cell Biochem 1994 Jun 15
PMID:Role of regulatory proteins (troponin-tropomyosin) in pathologic states. 781 55

We have examined changes in the expression of chicken myosin heavy chain (MHC) mRNAs in the heart and skeletal muscles during normal development and in regenerating adult muscles. cDNA clones isolated from adult heart and regenerating skeletal muscle libraries revealed more than 98% sequence homology in the 3' untranslated regions. Using specific cDNA probes we have detected ventricular MHC transcripts in the heart and in early developmental stages of fast as well as slow skeletal muscles. The expression of ventricular MHC mRNA in skeletal muscles is especially significant since, in contrast to mammals, the avian ventricular and slow MHC mRNAs are encoded by different genes.
Cell Mol Biol Res 1994
PMID:Cardiac phenotypic markers expressed in early stages of both cardiac and skeletal muscle development. 784 68

The actin cytoskeleton cells is altered in rvs161 mutant yeast, with the defect becoming more pronounced under unfavorable growth conditions, as described for the rvs167 mutant. The cytoskeletal alteration has no apparent effect on invertase secretion and polarized growth. Mutations in RVS161, just as in RVS167, lead to a random budding pattern in a/alpha diploid cells. This behavior is not observed in a/a diploid cells homozygous for the rvs161-1 or rvs167-1 mutations. In addition, sequence comparisons revealed that amphiphysin, a protein first found in synaptic vesicles of chicken and shown to be the autoantigen of Stiff Man syndrome, presents similarity with both Rvs proteins. Furthermore, limited similarities with myosin heavy chain and tropomyosin alpha chain from higher eukaryotic cells allow for the definition of a possible consensus sequence. The finding of related sequences suggests the existence of a function for these proteins that is conserved among eukaryotic organisms.
Mol Gen Genet 1995 Feb 20
PMID:Actin cytoskeleton and budding pattern are altered in the yeast rvs161 mutant: the Rvs161 protein shares common domains with the brain protein amphiphysin. 789 62


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