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

This paper examines the quantitative relationship between the expression of myosin heavy chain (MHC) and actin at both the levels of their mRNAs and their proteins. Explanted human left ventricle tissues were obtained from non-diseased (ND) individuals and from dilated cardiomyopathy (DCM) patients with terminally failing hearts who underwent heart transplantation. We found: (1) there are substantial differences in the stoichiometry of sarcomeric MHC and actin transcripts in hearts of DCM patients as well as in ND individuals; (2) there are substantial differences between levels of total sarcomeric actin transcripts from different individual patients; (3) by and large variations in transcript levels between samples from the same heart are much less than between samples from different hearts; and (4) the ratio of MHC to sarcomeric actin proteins expressed by different ND and DCM hearts remains essentially constant. We conclude that the human ventricle can accommodate a substantial imbalance between sarcomeric MHC and actin mRNA levels while maintaining a constant ratio of their corresponding proteins.
J Mol Cell Cardiol 1997 Mar
PMID:Variations in the relative mRNA levels of actins and myosin heavy chains do not produce corresponding differences in their proteins in the adult human heart. 915 50

In order to set the basis for detailed clinical investigations, mitochondrial creatine kinase (Mi-CK) was purified to homogeneity from human cardiac muscle. Biophysical characterization by SDS-PAGE, gel permeation chromatography and by electron microscopy of negatively stained single molecules demonstrated that, similar to other vertebrate Mi-CKs, human sarcomeric Mi-CK occurs in two different oligomeric forms, dimers and octamers, that are readily interconvertible. The apparent MTs of Mi-CK protomers, dimers and octamers were 43,600 +/- 800, 79,700 +/- 800 and 371,000 +/- 3000, respectively. In addition, isoelectric focussing proved to be a suitable technique for routinely distinguishing Mi-CK from cytosolic MM-CK and gave pl values of 8.30 +/- 0.04 and 7.44 +/- 0.04 for octameric and dimeric human sarcomeric Mi-CK. Circumstantial evidence suggests that both the highly symmetrical structure and the high pI value of Mi-CK octamers are crucial determinants for the physiological functions of this enzyme.
J Mol Cell Cardiol 1997 Mar
PMID:Purification and characterization of human sarcomeric mitochondrial creatine kinase. 915 53

Transcription of sarcomeric alpha-actin genes is developmentally regulated during skeletal and cardiac muscle development through fine-tuned control mechanisms involving multiple cooperative and antagonistic transcription factors. Among the cis-acting DNA elements recognized by these factors is the sequence CC(A/T)6GG of the serum response element (SRE), which is present in a number of growth factor-inducible and myogenic specified genes. We recently showed that the cardiogenic homeodomain factor, Nkx-2.5, served as a positive acting accessory factor for serum response factor (SRF) and together provided strong transcriptional activation of the cardiac alpha-actin promoter. In addition, Nkx-2.5 and SRF collaborated to activate the endogenous murine cardiac alpha-actin gene in 10T1/2 fibroblasts, by a mechanism that involved coassociation of SRF and Nkx-2.5 on intact SREs of the alpha-actin promoter. Here, we show that the second SRE of the avian cardiac alpha-actin promoter served as a binding site for Nkx-2.5, SRF, and zinc finger containing GLI-Kruppel-like factor, YY1. Expression of YY1 inhibited cardiac alpha-actin promoter activity, whereas coexpression of Nkx-2.5 and SRF was able to partially reverse YY1 repression. Displacement of YY1 binding by Nkx-2.5/SRF complex occurs through mutually exclusive binding across the CaSRE2. The interplay and functional antagonism between YY1 and Nkx-2.5/SRF might constitute a developmental as well as a physiologically regulated mechanism that modulates cardiac alpha-actin gene expression during cardiogenesis.
Mol Endocrinol 1997 Jun
PMID:Competition between negative acting YY1 versus positive acting serum response factor and tinman homologue Nkx-2.5 regulates cardiac alpha-actin promoter activity. 917 Dec 44

We examined changes in the structural and physiological characteristics of human atrial myocytes during primary culture in the presence of serum. Action potentials and ionic currents were recorded in freshly dissociated (FM) and cultured (CM) whole-cell patch-clamped myocytes, alpha-smooth muscle actin, sarcomeric alpha-actinin and beta-myosin heavy chains (beta-MHC) were stained with monoclonal antibodies. From day 5 to day 21, myocytes lost their rod shape, spread and exhibited reorganized sarcomeres. These morphological changes were associated with a marked increase in membrane capacitance (+266%). Both beta-MHC and alpha-smooth muscle actin were expressed in CM but not in FM, indicating a dedifferentiation process. CM were characterized by a lower resting potential (-30 +/- 2 v -60 +/- 4 mV, P < 0.05) and, when repolarized, by a shorter action potential duration (APD) than FM (APD-60: 126.9 v 159.6 ms, P < 0.05). The inward rectifier K+ current was absent in CM, thus explaining the low resting potential. The density of the transient component of the voltage-activated K+ current Ito1 was not modified during culture, while that of the sustained component Isus was increased fourfold. The amplitude of ICa was increased, but its density was unchanged, indicating that CM maintained a normal density of functional calcium channels. Neither the voltage dependence nor the inactivation of ICa was modified in CM. The time constants of inactivation of ICa were unchanged, although the amplitude of the rapidly inactivating component of ICa was increased in CM compared to FM. Moreover, ICa was increased by the beta-adrenergic agonist isoproterenol (1 microM) throughout the culture period. Our results demonstrate that in long-term serum-supplemented culture, adaptation of human atrial myocytes to their new environment is associated with differential alterations of the main ionic currents and phenotypic changes characteristic of immature myocardium.
J Mol Cell Cardiol 1997 May
PMID:Primary culture of human atrial myocytes is associated with the appearance of structural and functional characteristics of immature myocardium. 920 17

Neonatal cardiac myocytes continue to undergo nuclear division, but lose their ability to complete cell division between 3 and 4 days of age. To examine cytoskeletal organisation of cardiac myocytes during mitosis, freshly isolated cardiac myocytes from 2-, 4-, 6- and 8-day-old rats were fixed and labeled with anti-tubulin, vinculin, desmin and sarcomeric alpha-actinin antibodies. The central, nuclear region of cardiac myocytes is expanded to form a balloon-like structure when they entered prophase. The organisation of microtubules, vinculin and desmin in mitotic myocytes from 4-, 6- and 8-day-old rats was identical to that in dividing myocytes from 2-day-old animals. Microtubules emanating from the nuclear membrane mainly ran along the longitudinal axis of cardiac myocytes in interphase. Microtubules were disassembled and reorganised into the mitotic spindle during mitosis. Desmin was disassembled, either diffusely distributed in the cytoplasm or formed spotty cytoplasmic aggregates during mitosis. Vinculin was disassembled in prometaphase, diffusely distributed in the cytoplasm and associated with cell membranes. During telophase it concentrated in the equator of mitotic spindles. Sarcomeric alpha-actinin became dispersed in the cytoplasm of mitotic myocytes from 2-day-old rats in prometaphase. It remained diffusely distributed in the cytoplasm and associated with cell membranes until the completion of cytokinesis. However, sarcomeric alpha-actinin was only partially disassembled in 4-, 6- and 8-day-old myocytes. Striations of alpha-actinin with full sarcomere length were observed in the cytoplasm as well as in the region of furrow formation. Thus, incomplete disassembly and presence of myofibrils in the equator region where cleavage furrows from may physically impede the furrowing of sarcolemma driven by the contractile ring, resulting in the formation of binucleated cardiac myocytes.
J Mol Cell Cardiol 1997 Jun
PMID:Formation of binucleated cardiac myocytes in rat heart: II. Cytoskeletal organisation. 922 Mar 41

The reactivation of an embryonic pattern of gene expression is a central feature common to virtually all forms of cardiac hypertrophy. Unraveling the regulatory mechanisms, growth factors and cytokines controlling gene expression and cell fate during cardiac development may therefore have implications for our understanding of cardiac hypertrophy in the adult. Along this line, a cDNA expression library was established from an embryonic stem cell-based in vitro model of cardiogenesis, and screened for clones that would induce an increase in cell size in cultured cardiomyocytes. This experimental strategy resulted in the isolation of a novel cytokine, cardiotrophin-1 (CT-1), that activates several features of cardiomyocyte hypertrophy in vitro, including sarcomeric organization and embryonic gene expression. CT-1 displays structural similarities to the interleukin (IL)-6 related cytokines. Furthermore, receptor binding studies and functional studies reveal that CT-1 shares the signal transducing receptor components gp130 and LIFR with the previously identified members of the IL-6 cytokine family. CT-1 rapidly activates gp130 and LIFR tyrosine phosphorylation in cultured cardiac myocytes. The growth promoting effects of CT-1 therefore indicate that signaling pathways emanating from gp130 and LIFR are coupled to cardiomyocyte hypertrophy. In support of this notion, the simultaneous overexpression of IL-6 and the IL-6 receptor in transgenic mice has been shown to result in a constitutive tyrosine phosphorylation of gp130 in the myocardium and cardiac hypertrophy. The striking phenotype of gp130 null-mutant mice, generated by homologous recombination, implies gp130 in cardiac development as well: mutant mice exhibit severe ventricular hypoplasia, suggesting a role for gp130-dependent signaling pathways in the expansion of the compact layer of the ventricular myocardium. CT-1 is expressed at high levels in the myocardium during the course of cardiogenesis, and promotes the proliferation and survival of embryonic cardiomyocytes. CT-1 may therefore represent a candidate cytokine to activate gp130 during cardiac development. In summary, cytokines signaling through gp130 are emerging as potent regulators of embryonic heart development and adult cardiac hypertrophy.
J Mol Med (Berl) 1997 Jul
PMID:Cardiotrophin-1 and the role of gp130-dependent signaling pathways in cardiac growth and development. 925 12

Neonatal and adult rat cardiomyocytes display differences when isolated and cultured in vitro. Whereas cells obtained from juvenile hearts adapt quite rapidly as judged by their beating, cells from adult animals undergo a complex degeneration-regeneration process of their myofibrillar apparatus. These differences are also reflected by a distinct sensitivity to drugs that affect the non-sarcomeric cytoskeleton. After long-term treatment with nocodazole, which disassembles microtubules, neonatal rat cardiomyocytes (NRC) remain relatively unaffected, whereas adult rat cardiomyocytes (ARC) are unable to spread on the substrate or to undergo the remodelling process of their myofibrils. If microfilaments are destroyed by cytochalasin D, neither NRC nor ARC spread, and they lose the capacity to assemble new myofibrils. The effects of drug treatment with both cytochalasin and nocodazole, respectively, were reversible, since normal myofibrillogenesis took place after the cells had been washed and cultivated in standard medium for 4 days. This study demonstrates that microfilaments are essential for assembly of new sarcomeres in vitro, and underlines intrinsic differences between NRC and ARC in their requirement for intact microtubules. Adult cardiomyocytes have lost a certain degree of flexibility due to their longer adaptation to the specific situation in the heart, whereas cardiomyocytes isolated from neonatal animals can maintain and assemble myofibrils in vitro even after their microtubules were destroyed.
J Mol Cell Cardiol 1998 Jan
PMID:Different behaviour of the non-sarcomeric cytoskeleton in neonatal and adult rat cardiomyocytes. 950 Aug 78

The huge modular protein nebulin is located in the thin filament of striated muscle in vertebrates and is thought to bind and stabilize F-actin. The C-terminal part of human nebulin is anchored in the sarcomeric Z-disk and contains an SH3 domain, the first of such motifs to be identified in a myofibrillar protein. We have determined the nebulin SH3 sequence from several species and found it strikingly conserved. We have also shown that the SH3 transcripts are constitutively expressed in skeletal muscle tissues. As the first step towards a molecular understanding of nebulin's cellular role we have determined the three-dimensional structure of the human nebulin SH3 domain in solution by nuclear magnetic resonance (NMR) spectroscopy and compared it with other known SH3 structures. The nebulin SH3 domain has a well-defined structure in solution with a typical SH3 topology, consisting of a beta-sandwich of two triple-stranded, antiparallel beta-sheets arranged at right angles to each other and of a single turn of a 310-helix. An additional double-stranded antiparallel beta-sheet in the RT loop bends over the beta-sandwich. The derived structure reveals a remarkable similarity with a distinct subset of SH3 domains, especially in the structural features of the exposed hydrophobic patch that is thought to be the site of interaction with polyproline ligands. On the basis of this similarity, we have modelled the interaction with an appropriate polyproline ligand and attempted to delineate the characteristics of the physiological SH3-binding partner in the Z-disk. Our results represent the first step in reconstructing the structure of nebulin and are expected to contribute to our understanding of nebulin's functional role in myofibrillar assembly.
J Mol Biol 1998 Feb 13
PMID:SH3 in muscles: solution structure of the SH3 domain from nebulin. 951 27

The myofibrils of cross-striated muscle fibers contain in their M bands cytoskeletal proteins whose main function seems to be the stabilization of the three-dimensional arrangement of thick filaments. We identified two immunoglobin domains (Mp2-Mp3) of M-protein as a site binding to the central region of light meromyosin. This binding is regulated in vitro by phosphorylation of a single serine residue (Ser76) in the immediately adjacent amino-terminal domain Mp1. M-protein phosphorylation by cAMP-dependent kinase A inhibits binding to myosin LMM. Transient transfection studies of cultured cells revealed that the myosin-binding site seems involved in the targeting of M-protein to its location in the myofibril. Using the same method, a second myofibril-binding site was uncovered in domains Mp9-Mp13. These results support the view that specific phosphorylation events could be also important for the control of sarcomeric M band formation and remodeling.
Mol Biol Cell 1998 Apr
PMID:Mapping of a myosin-binding domain and a regulatory phosphorylation site in M-protein, a structural protein of the sarcomeric M band. 952 81

Five disease genes encoding sarcomeric proteins and associated with familial and classical forms of hypertrophic cardiomyopathy have been determined since 1989. In 1996 two other genes encoding ventricular regulatory and essential myosin light chains were shown to be associated with a particular phenotype of the disease characterized by mid left ventricular obstruction. The aim of the present study was to search for mutations in the ventricular regulatory myosin light chain gene (MYL2), located on chromosome 12q23q24.3, in a panel of 42 probands presenting a classical phenotype of familial hypertrophic cardiomyopathy. Single-strand conformation polymorphism analysis was used to search for mutations in the coding segments of the MYL2 gene, and the abnormal products were sequenced. Two novel missense mutations, Phe18Leu in exon 2 and Arg58Gln in exon 4 were identified in three unrelated families. None of the affected patients had hypertrophy localized only at the level of the papillary muscle with mid left ventricular obstruction. By analysis of genetic recombinations, one of these mutations identified in a large family allowed us to refine the localization of the MYL2 gene on the genetic map, in an interval of 6 cM containing six informative microsatellite markers. In conclusion, we show that mutations in the MYL2 gene may be involved in familial and classical forms of hypertrophic cardiomyopathy, and we provide new tools for the genetic analysis of patients with familial hypertrophic cardiomyopathy.
J Mol Med (Berl) 1998 Mar
PMID:Identification of two novel mutations in the ventricular regulatory myosin light chain gene (MYL2) associated with familial and classical forms of hypertrophic cardiomyopathy. 953 54


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>