Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The therapeutic use of doxorubicin (an antitumoral antibiotic belonging to the anthracycline group) is limited by its cardiotoxicity. Adriamycin (DXR) causes myocardial subcellular damage, such as myocytolysis, disarray of actin filaments, and alterations in the Z-band with loss of sarcomeric organization. We studied the effect of stoichiometrical concentrations of DXR on the interaction between cardiac actin and alpha-actinin in solution. Doxorubicin inhibits the formation of alpha-actinin/actin tridimensional networks and bundles. The main effect of the drug seems to be on the size of the actin polymers.
Exp Mol Pathol 1992 Jun
PMID:Interaction of cardiac alpha-actinin and actin in the presence of doxorubicin. 163 82

A single-site mutation of the flight-muscle-specific actin gene of Drosophila melanogaster causes a substitution of glutamic acid 93 by lysine in all the actin encoded in the indirect flight muscle (IFM). In these Act88FE93K mutants, myofibrillar bundles of thick and thin filaments are present but lack Z-discs and all sarcomeric repeats. Dense filament bundles, which are probably aberrant Z-discs, are seen in myofibrils of pupal flies, but early in adult life these move to the periphery of the fibrils and are not seen in skinned adult fibres. Consistent with this observation, alpha-actinin and other high molecular weight proteins, possibly associated with Z-discs, are not detected on SDS/polyacrylamide gels or Western blots of skinned adult IFM. The mutation lies at the beginning of a loop in the small domain of actin, near the myosin binding region. However, that the mutant actin binds myosin heads is shown by (1) rigor crossbridges in electron micrographs, (2) the appropriate rise in stiffness when ATP is withdrawn in mechanical experiments, and (3) equal protection against tryptic digestion provided by rigor binding between actin and myosin in both wild-type and mutant fibres. Reversal of rigor chevron angle along some thin filaments reflects reversal of thin-filament polarity due to lattice disorder. The absence of Z-discs, alpha-actinin and two high molecular weight proteins, and binding studies by others, suggest that the substitution at residue 93 affects the binding of the mutant actin to a protein, possibly alpha-actinin, which is necessary for Z-disc assembly or maintenance.
J Mol Biol 1991 Dec 20
PMID:Functional and ultrastructural effects of a missense mutation in the indirect flight muscle-specific actin gene of Drosophila melanogaster. 168 24

The two sarcomeric actin genes, encoding alpha-cardiac and alpha-skeletal actins, are co-expressed in striated muscle, but in the adult the respective isoform predominates in cardiac or skeletal muscle of the normal mouse. We have investigated the interaction between this gene pair in different genetic contexts. Northern blot analysis of alpha-actin mRNA levels in different inbred mice (129/SJ, C3H, C57BL/6) demonstrates variation of as much as threefold in skeletal muscle and eightfold in cardiac muscle. High or low-level expression is seen for both skeletal and cardiac muscle in a given line, suggesting common regulatory phenomena affecting the abundant alpha-skeletal or alpha-cardiac transcript. In the BALB/c mouse, which has a mutant cardiac actin locus, skeletal as well as cardiac actin mRNA and protein accumulate in the adult heart. We have analysed the role of the two alpha-actin genes in this phenomenon in seven recombinant inbred mouse lines (BALB/c x C57BL/6) and in a cross (BALB/c x C3H). The results demonstrate that neither alpha-actin gene alone is sufficient, and implicate other regulatory loci. DNA sequencing of the C3H and BALB/c alpha-skeletal actin gene promoters shows that they are virtually identical over 830 nucleotides. The relative levels of alpha-skeletal and alpha-cardiac actin proteins have been measured by N-terminal peptide analysis in the different mouse lines. The results point to regulatory loci affecting mRNA utilization and protein stability.
J Mol Biol 1990 Feb 20
PMID:Genetic analysis of the interaction between cardiac and skeletal actin gene expression in striated muscle of the mouse. 169 Mar 2

We have isolated and characterized five overlapping clones that encompass 3.2 kb and encode a part of the short subfragment 2, the hinge, and the light meromyosin regions of the myosin heavy chain rod as well as 143 bp of the 3' untranslated portion of the mRNA. Northern blot analysis showed expression of this mRNA mainly in ventricular muscle of the adult chicken heart, with trace levels detected in the atrium. Transient expression was seen in skeletal muscle during development and in regenerating skeletal muscle following freeze injury. To our knowledge, this is the first report of an avian ventricular myosin heavy chain sequence. Phylogenetic analysis indicated that this isoform is a distant homolog of other ventricular and skeletal muscle myosin heavy chains and represents a distinct member of the multigene family of sarcomeric myosin heavy chains. The ventricular myosin heavy chain of the chicken is either paralogous to its counterpart in other vertebrates or has diverged at a significantly higher rate.
J Mol Evol 1991 Oct
PMID:Structural and phylogenetic analysis of the chicken ventricular myosin heavy chain rod. 177 88

Hyperthyroid treatment produces rapid cardiac cell hypertrophy with all subcellular components increasing in an orderly manner. We compare normal and hyperthyroid tissue in order to relate changes in distribution of myosin mRNA during rapid assembly of myofibrils. At the light microscopic level, in situ hybridization of the ventricular cells shows myosin heavy chain mRNA to be distributed in a spoke-like pattern radiating from the nucleus. Electron microscopy provides the higher resolution necessary to determine mRNA distribution with respect to adjacent sarcomeric and cytoskeletal structures. Papillary muscles were removed from hyperthyroid and normal rabbits, aldehyde fixed, and embedded in LR white. Biotinated riboprobe transcribed from 0.5 kb in the coding region of terminal portion of the rod of alpha-myosin was hybridized and detected by immunocytochemical methods using 5 nm immunoglobulin G gold conjugates. Electron microscopy in situ hybridization runs with same-sense and anti-sense riboprobes were processed and ten micrographs randomly taken from each. Specific cytoplasmic densities of myosin mRNA were calculated by counting clusters of five or more gold particles over respective tissue components after subtraction of background counts. For both normal myocytes and hyperthyroid myocytes, the density of myosin mRNA was about 15 times higher in the cytoskeletal-rich inter-myofibrillar space than in the myofibrils. About half of the myosin mRNA in this inter-myofibrillar region is found within 10 nm of the peripheral filament, but no excess sarcomeric accumulation was seen beside the A-Band. It appears that most of the myosin is translated from mRNA within the inter-myofibrillar space along the entire length of the myofibril periphery. The emerging myosin heavy chain is not directly anchored to the thick filaments in either normal or rapidly growing cardiac cells.
J Mol Cell Cardiol 1991 Mar
PMID:Distribution of myosin heavy chain mRNA in normal and hyperthyroid heart. 188 Aug 13

Three upstream CBAR cis-acting promoter elements, containing the inner core CC(A/T)6GG of the serum response element (SRE), are required for myogenic cell type-restricted expression of the avian skeletal alpha-actin gene (K.L. Chow and R.J. Schwartz, Mol. Cell. Biol. 10:528-538, 1990). These actin SRE elements display differential binding properties with two distinct nuclear proteins, serum response factor (SRF) and another factor described here as F-ACT1. SRF is able to bind to all actin SREs with various affinities. This multisite interaction is marked by cooperative binding events in that the two high-affinity proximal and distal SREs facilitate the weak central-site interaction with SRF, leading to the formation of a higher-order SRF-promoter complex. Functional analyses reveal that undisrupted multiple SRF-DNA interactions are absolutely essential for promoter activity in myogenic cells. F-ACT1, present at higher levels in nonmyogenic cells and replicating myoblasts than in myotubes, binds solely to the proximal SRE, and its binding is mutually exclusive with that of SRF owing to their overlapping base contacts. The cooperative promoter binding by SRF, however, can effectively displace prebound F-ACT1. In addition, an intact F-ACT1 binding site acts as a negative promoter element by restricting developmentally timed expression in myoblasts. F-ACT1 may therefore act as a repressor of skeletal alpha-actin gene transcription. This interplay between F-ACT1 and SRF may constitute a developmental as well as a physiologically regulated mechanism which modulates sarcomeric actin gene expression.
Mol Cell Biol 1991 Oct
PMID:Activation of skeletal alpha-actin gene transcription: the cooperative formation of serum response factor-binding complexes over positive cis-acting promoter serum response elements displaces a negative-acting nuclear factor enriched in replicating myoblasts and nonmyogenic cells. 192 33

This is a qualitative and quantitative study of dog bundle branch and Purkinje cell development from day 0 to week 12 of life; we correlate the morphologic data with changes observed in the functional properties of developing dog Purkinje tissue. The bundle branch itself has a roughly cylindrical shape and is surrounded by a collagen sheath covered with endocardium. Within the bundle, Purkinje cells are packed closely together in fascicles distributed evenly around a central artery. Cross-sectional area doubles in the right bundle and increases 5-fold in the left bundle system between day 0 and week 12 of life. About one third of the bundle by volume is Purkinje tissue; the rest is extracellular space containing an increasing amount of collagen as the animal ages. Purkinje cell cross-sectional area is constant during the first week of life, but its length doubles and the cell changes from a relatively round to a more cylindrical shape. Between day 7 and week 12, cell diameter doubles; Purkinje cell surface area increases 5-fold and its volume almost 10-fold. As a consequence, the surface to volume ratio halves and approaches the value reported for adult dogs by week 12 of life. The percent of the intercalated disc occupied by nexal junctions virtually doubles by week 12, the same period over which Purkinje fiber conduction velocity increases. The disc itself becomes less dominant as the cell enlarges; the total percent of sarcolemma involved in its formation decreases by a fourth and has achieved the adult value by week 12 of life. As this happens, the percent of cell membrane facing on clefts increases almost 6-fold, so that the total percent of sarcolemma facing on small spaces (approximately 340A wide) is constant over the age period studied. The paucity of clefts in newborn tissue compared with the value reported for the adult dog may help explain the relative lack of responsiveness to extracellular potassium concentration of the resting membrane potential described for fetal Purkinje tissue. Within the Purkinje cell itself, the percent by volume occupied by mitochondria remains relatively constant over the age span studied, while sarcomeric mass increases 3-fold over the same period of time; these data are consonant with the relative resistance of this tissue to hypoxia.
J Mol Cell Cardiol 1991 Sep
PMID:The morphology of the developing canine conducting system: bundle branch and Purkinje cell architecture from birth to week 12 of life. 194 96

The purpose of this study was to characterize the complete cDNA sequence encoding the rabbit smooth muscle myosin heavy chain (MHC) and determine the exon/intron organization at the 5' end of the corresponding gene. The full-length cDNA sequence of 6644 base pairs encoding a protein of 1972 amino acids was generated from two cDNA clones: PBRUC1 (approximately 6.3 kilobases), isolated from a rabbit uterus cDNA library, and PBRU-PCR33 (420 base pairs), produced by primer extension and PCR amplification. Compared with the chicken smooth muscle MHC sequence [Yanagisawa, M., Hamada, Y., Katsuragawa, Y., Imamura, M., Mikawa, T. & Masaki, T. (1987) J. Mol. Biol. 198, 143-157] the rabbit MHC shares about 90% amino acid identity in the S1 globular head region but shows a striking sequence divergence at the junction between the 25-kDa and 50-kDa proteolytic fragments of the functionally important S1 head domain. Genomic cloning shows that the rabbit smooth muscle MHC gene is large and has an unusual exon/intron organization at the 5' end. The first eight contiguous exons are located within a region of at least 70 kilobases of genomic DNA. Some introns span several kilobases of DNA and others at the 5' end show a high degree of intron conservation in the Mg(2+)-ATPase domain when compared with more distantly related sarcomeric MHC genes. Primer extension and S1 nuclease mapping analysis demonstrate that transcription initiates from a single site in the rabbit smooth muscle MHC gene.
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PMID:Characterization of a mammalian smooth muscle myosin heavy-chain gene: complete nucleotide and protein coding sequence and analysis of the 5' end of the gene. 196 35

The cardiac troponin T (cTNT) promoter contains a highly muscle specific distal promoter element capable of conferring muscle-specific transcription from a heterologous TATA box-transcription initiation site. Three sequence motifs within this distal promoter element are conserved in the promoter and regulatory regions of many sarcomeric protein genes. Mutational analysis demonstrated that homologies to two of these conserved motifs (CArG/CBAR and MEF 1) were not required for activity of cTNT promoter-marker gene constructs in transfected embryonic skeletal muscle cells. In contrast, disruption of either or both copies of the conserved M-CAT motif (5'-CATTCCT-3') inactivated the cTNT promoter in these cells. Both M-CAT motifs were protected from DNase I cleavage in solution footprint assays by an M-CAT binding factor (MCBF) present in nuclear extracts from embryonic muscle tissue. M-CAT mutations that inactivated the cTNT promoter also disrupted MCBF binding, indicating that MCBF may be a key trans-acting factor required for muscle-specific expression of the cTNT promoter. MCBF also bound to the M-CAT motif in the distal promoter region of the skeletal alpha-actin gene, suggesting that it may play a role in the regulation of this and perhaps other muscle genes that contain M-CAT motifs.
Mol Cell Biol 1990 Aug
PMID:M-CAT binding factor, a novel trans-acting factor governing muscle-specific transcription. 237 Aug 66

Actin is known to be synthesized both during oogenesis and in cleavage-stage embryos in mice. Cytoskeletal beta-actin appears to be the major component, followed by gamma-actin, but the synthesis of alpha-actin has also been inferred from protein electrophoretic patterns. We have studied the expression of cytoskeletal (beta- and gamma-) and sarcomeric (alpha-cardiac and alpha-skeletal) actin genes at the level of the individual mRNAs in blot hybridization experiments using isoform-specific RNA probes. The results show that there are about 2 x 10(4) beta-actin mRNA molecules in the fully grown oocyte; this number drops to about one-half in the egg and less than one-tenth in the late two-cell embryo but increases rapidly during cleavage to about 3 x 10(5) molecules in the late blastocyst. The amount of gamma-actin mRNA is similar to that of beta-actin in oocytes and eggs but only about 40% as much in late blastocysts, indicating a differential accumulation of these mRNAs during cleavage. The developmental pattern of beta- and gamma-actin mRNA provides a striking example of the transition from maternal to embryonic control that occurs at the two-cell stage and involves the elimination of most or all of the maternal actin mRNA. There was no detectable alpha-cardiac or alpha-skeletal mRNA (i.e., less than 1,000 molecules per embryo) at any stage from oocyte to late blastocyst, suggesting that the sarcomeric actin genes are silent during preimplantation development.
Mol Reprod Dev 1990 Jun
PMID:Quantitative changes in cytoskeletal beta- and gamma-actin mRNAs and apparent absence of sarcomeric actin gene transcripts in early mouse embryos. 237 94


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