174 results found
Schneider MD, Gaussin V, Lyons KM, 2003, Tempting fate: BMP signals for cardiac morphogenesis, CYTOKINE & GROWTH FACTOR REVIEWS, Vol: 14, Pages: 1-4, ISSN: 1359-6101
Sano M, Schneider MD, 2003, Cyclins That Don't Cycle Cyclin T/Cyclin-Dependent Kinase-9 Determines Cardiac Muscle Cell Size, CELL CYCLE, Vol: 2, Pages: 99-104, ISSN: 1538-4101
Bonow R, Clark EB, Curfman GD, et al., 2002, Task force on strategic research direction - Clinical science subgroup - Key science topics report, CIRCULATION, Vol: 106, Pages: E162-E166, ISSN: 0009-7322
Sano M, Abdellatif M, Oh H, et al., 2002, Activation and function of cyclin T-Cdk9 (positive transcription elongation factor-b) in cardiac muscle-cell hypertrophy, NATURE MEDICINE, Vol: 8, Pages: 1310-1317, ISSN: 1078-8956
Minamino T, Yujiri T, Terada N, et al., 2002, MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 99, Pages: 3866-3871, ISSN: 0027-8424
Gaussin V, Van de Putte T, Mishina Y, et al., 2002, Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3., Proc Natl Acad Sci U S A, Vol: 99, Pages: 2878-2883, ISSN: 0027-8424
Receptors for bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta (TGFbeta) superfamily, are persistently expressed during cardiac development, yet mice lacking type II or type IA BMP receptors die at gastrulation and cannot be used to assess potential later roles in creation of the heart. Here, we used a Cre/lox system for cardiac myocyte-specific deletion of the type IA BMP receptor, ALK3. ALK3 was specifically required at mid-gestation for normal development of the trabeculae, compact myocardium, interventricular septum, and endocardial cushion. Cardiac muscle lacking ALK3 was specifically deficient in expressing TGFbeta2, an established paracrine mediator of cushion morphogenesis. Hence, ALK3 is essential, beyond just the egg cylinder stage, for myocyte-dependent functions and signals in cardiac organogenesis.
Gaussin V, Van de Putte T, Mishina Y, et al., 2002, Endocardial cushion and myocardial defects after cardiac myocyte-specific conditional deletion of the bone morphogenetic protein receptor ALK3, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 99, Pages: 2878-2883, ISSN: 0027-8424
Schneider MD, 2002, Serial killer: angiotensin drives cardiac hypertrophy via TGF-beta 1, JOURNAL OF CLINICAL INVESTIGATION, Vol: 109, Pages: 715-716, ISSN: 0021-9738
Sano M, Schneider MD, 2002, Still stressed out but doing fine - Normalization of wall stress is superfluous to maintaining cardiac function in chronic pressure overload, CIRCULATION, Vol: 105, Pages: 8-10, ISSN: 0009-7322
de Longh RU, Lovicu FJ, Overbeek PA, et al., 2001, Requirement for TGF beta receptor signaling during terminal lens fiber differentiation, DEVELOPMENT, Vol: 128, Pages: 3995-4010, ISSN: 0950-1991
Oh H, Taffet GE, Youker KA, et al., 2001, Telomerase reverse transcriptase promotes cardiac muscle cell proliferation, hypertrophy, and survival, PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, Vol: 98, Pages: 10308-10313, ISSN: 0027-8424
Schneider MD, Lorell BH, 2001, AT(2), judgment day - Which angiotensin receptor is the culprit in cardiac hypertrophy?, CIRCULATION, Vol: 104, Pages: 247-248, ISSN: 0009-7322
Schneider MD, Lorell BH, 2001, AT 2 , Judgment Day, Circulation, Vol: 104, Pages: 247-248, ISSN: 0009-7322
Wurthner JU, Frank DB, Felici A, et al., 2001, Transforming growth factor-beta receptor-associated protein 1 is a Smad4 chaperone, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 276, Pages: 19495-19502, ISSN: 0021-9258
Minamino T, Gaussin V, DeMayo FJ, et al., 2001, Inducible gene targeting in postnatal myocardium by cardiac-specific expression of a hormone-activated Cre fusion protein, CIRCULATION RESEARCH, Vol: 88, Pages: 587-592, ISSN: 0009-7330
Schneider MD, MacLellan WR, 2001, Cyclin-dependent kinase-2 in the birth and death of cardiac muscle cells, CIRCULATION RESEARCH, Vol: 88, Pages: 367-369, ISSN: 0009-7330
Gutstein DE, Morley GE, Tamaddon H, et al., 2001, Conduction slowing and sudden arrhythmic death in mice with cardiac-restricted inactivation of connexin43, CIRCULATION RESEARCH, Vol: 88, Pages: 333-339, ISSN: 0009-7330
Schneider MD, Schwartz RJ, 2000, Chips ahoy - Gene expression in failing hearts surveyed by high-density microarrays, CIRCULATION, Vol: 102, Pages: 3026-3027, ISSN: 0009-7322
MacLellan WR, Xiao G, Abdellatif M, et al., 2000, A novel Rb- and p300-binding protein inhibits transactivation by MyoD, MOLECULAR AND CELLULAR BIOLOGY, Vol: 20, Pages: 8903-8915, ISSN: 0270-7306
Zhang D, Gaussin V, Taffet GE, et al., 2000, TAK1 is activated in the myocardium after pressure overload and is sufficient to provoke heart failure in transgenic mice, NATURE MEDICINE, Vol: 6, Pages: 556-563, ISSN: 1078-8956
MacLellan WR, Schneider MD, 2000, Genetic dissection of cardiac growth control pathways, ANNUAL REVIEW OF PHYSIOLOGY, Vol: 62, Pages: 289-319, ISSN: 0066-4278
Akli S, Zhan S, Abdellatif M, et al., 1999, E1A can provoke G1 exit that is refractory to p21 and independent of activating cdk2., Circ Res, Vol: 85, Pages: 319-328, ISSN: 0009-7330
E1A can evoke G1 exit in cardiac myocytes and other cell types by displacing E2F transcription factors from tumor suppressor "pocket" proteins and by a less well-characterized p300-dependent pathway. Bypassing pocket proteins (through overexpression of E2F-1) reproduces the effect of inactivating pocket proteins (through E1A binding); however, pocket proteins associate with a number of molecular targets apart from E2F. Hence, pocket protein binding by E1A might engage mechanisms for cell cycle reentry beyond those induced by E2F-1. To test this hypothesis, we used adenoviral gene transfer to express various E2F-1 and E1A proteins in neonatal rat cardiac myocytes that are already refractory to mitogenic serum, in the absence or presence of several complementary cell cycle inhibitors-p16, p21, or dominant-negative cyclin-dependent kinase-2 (Cdk2). Rb binding by E2F-1 was neither necessary nor sufficient for G1 exit, whereas DNA binding was required; thus, exogenous E2F-1 did not merely function by competing for the Rb "pocket." E2F-1-induced G1 exit was blocked by the "universal" Cdk inhibitor p21 but not by p16, a specific inhibitor of Cdk4/6; p21 was permissive for E2F-1 induction of cyclins E and A, but prevented their stimulation of Cdk2 kinase activity. In addition, E2F-1-induced G1 exit was blocked by dominant-negative Cdk2. Forced expression of cyclin E induced endogenous Cdk2 activity but not G1 exit. Thus, E2F-1-induced Cdk2 function was necessary, although not sufficient, to trigger DNA synthesis in cardiac muscle cells. In contrast, pocket protein-binding forms of E1A induced G1 exit that was resistant to inhibition by p21, whereas G1 exit via the E1A p300 pathway was sensitive to inhibition by p21. Both E1A pathways-via pocket proteins and via p300-upregulated cyclins E and A and Cdk2 activity, consistent with a role for Cdk2 in G1 exit induced by E1A. However, p21 blocked Cdk2 kinase activity induced by both E1A pathways equa
Abdellatif M, Packer SE, Michael LH, et al., 1998, A Ras-dependent pathway regulates RNA polymerase II phosphorylation in cardiac myocytes: implications for cardiac hypertrophy., Mol Cell Biol, Vol: 18, Pages: 6729-6736, ISSN: 0270-7306
Despite extensive evidence implicating Ras in cardiac muscle hypertrophy, the mechanisms involved are unclear. We previously reported that Ras, through an effector-like function of Ras GTPase-activating protein (GAP) in neonatal cardiac myocytes (M. Abdellatif et al., J. Biol. Chem. 269:15423-15426, 1994; M. Abdellatif and M. D. Schneider, J. Biol. Chem. 272:527-533, 1997), can up-regulate expression from a comprehensive set of promoters, including both cardiac cell-specific and constitutive ones. To investigate the mechanism(s) underlying these earlier findings, we have used recombinant adenoviruses harboring a dominant negative Ras (17N Ras) allele or the N-terminal domain of GAP (nGAP), responsible for the Ras-like effector function. Inhibition of endogenous Ras reduced basal levels of [3H]uridine and [3H]phenylalanine incorporation into total RNA, mRNA, and protein, with parallel changes in apparent cell size. In addition, 17N Ras markedly inhibited phosphorylation of the C-terminal domain (CTD) of RNA polymerase II (pol II), known to regulate transcript elongation, accompanied by down-regulation of its principal kinase, cyclin-dependent kinase 7 (Cdk7). In contrast, nGAP elicited the opposite effects on each of these parameters. Furthermore, cotransfection of constitutively active Ras (12R Ras) with wild-type pol II, rather than a truncated mutant lacking the CTD, demonstrated that Ras activation of transcription was dependent on the pol II CTD. Consistent with a potential role for this pathway in the development of cardiac myocyte hypertrophy, alpha1-adrenergic stimulation similarly enhanced pol II phosphorylation and Cdk7 expression, where both effects were inhibited by dominant negative Ras, while pressure overload hypertrophy led to an increase in both hyperphosphorylated and hypophosphorylated pol II in addition to Cdk7.
Charng MJ, Frenkel PA, Lin Q, et al., 1998, A constitutive mutation of ALK5 disrupts cardiac looping and morphogenesis in mice., Dev Biol, Vol: 199, Pages: 72-79, ISSN: 0012-1606
TGF beta family members are implicated in cardiac organogenesis, growth control, and positional information, including the direction of cardiac looping. However, genetic analysis of TGF beta signaling in mice has been confounded, in some cases, by noncardiac and generalized defects. Hence, deciphering TGF beta function in myocardium would benefit from cardiac-restricted mutations. We developed a constitutively activated type I receptor, ALK5L193A,P194A,T204D, and directed it to embryonic myocardium in transgenic mice. Expression of the activated ALK5 gene arrests looping morphogenesis and causes a linear, dilated, hypoplastic heart tube, despite normal expression of Nkx2.5 and dHAND, cardiogenic transcription factors whose absence provokes a similar phenotype. Ventricular hypoplasia was associated with precocious induction of the cyclin-dependent kinase inhibitor, p21. Thus, an ALK5-sensitive pathway mediates looping, perhaps through control of cardiac myocyte proliferation.
Charng MJ, Zhang D, Kinnunen P, et al., 1998, A novel protein distinguishes between quiescent and activated forms of the type I transforming growth factor beta receptor., J Biol Chem, Vol: 273, Pages: 9365-9368, ISSN: 0021-9258
Transforming growth factor beta (TGFbeta) signal transduction is mediated by two receptor Ser/Thr kinases acting in series, type II TGFbeta receptor (TbetaR-II) phosphorylating type I TGFbeta receptor (TbetaR-I). Because the failure of interaction cloning, thus far, to identify bona fide TbetaR-I substrates might reasonably have been due to the use of inactive TbetaR-I as bait, we sought to identify molecules that interact specifically with active TbetaR-I, employing the triple mutation L193A,P194A,T204D in a yeast two-hybrid system. The Leu-Pro substitutions prevent interaction with FK506-binding protein 12 (FKBP12), whose putative function in TGFbeta signaling we have previously disproved; the charge substitution at Thr204 constitutively activates TbetaR-I. Unlike previous screens using wild-type TbetaR-I, where FKBP12 predominated, none of the resulting colonies encoded FKBP12. A novel protein was identified, TbetaR-I-associated protein-1 (TRAP-1), that interacts in yeast specifically with mutationally activated TbetaR-I, but not wild-type TbetaR-I, TbetaR-II, or irrelevant proteins. In mammalian cells, TRAP-1 was co-precipitated only by mutationally activated TbetaR-I and ligand-activated TbetaR-I, but not wild-type TbetaR-I in the absence of TGFbeta. The partial TRAP-1 protein that specifically binds these mutationally and ligand-activated forms of TbetaR-I can inhibit signaling by the native receptor after stimulation with TGFbeta or by the constitutively activated receptor mutation, as measured by a TGFbeta-dependent reporter gene. Thus, TRAP-1 can distinguish activated forms of the receptor from wild-type receptor in the absence of TGFbeta and may potentially have a functional role in TGFbeta signaling.
Shou W, Aghdasi B, Armstrong DL, et al., 1998, Cardiac defects and altered ryanodine receptor function in mice lacking FKBP12., Nature, Vol: 391, Pages: 489-492, ISSN: 0028-0836
FKBP12, a cis-trans prolyl isomerase that binds the immunosuppressants FK506 and rapamycin, is ubiquitously expressed and interacts with proteins in several intracellular signal transduction systems. Although FKBP12 interacts with the cytoplasmic domains of type I receptors of the transforming growth factor-beta (TGF-beta) superfamily in vitro, the function of FKBP12 in TGF-beta superfamily signalling is controversial. FKBP12 also physically interacts stoichiometrically with multiple intracellular calcium release channels including the tetrameric skeletal muscle ryanodine receptor (RyR1). In contrast, the cardiac ryanodine receptor, RyR2, appears to bind selectively the FKBP12 homologue, FKBP12.6. To define the functions of FKBP12 in vivo, we generated mutant mice deficient in FKBP12 using embryonic stem (ES) cell technology. FKBP12-deficient mice have normal skeletal muscle but have severe dilated cardiomyopathy and ventricular septal defects that mimic a human congenital heart disorder, noncompaction of left ventricular myocardium. About 9% of the mutants exhibit exencephaly secondary to a defect in neural tube closure. Physiological studies demonstrate that FKBP12 is dispensable for TGF-beta-mediated signalling, but modulates the calcium release activity of both skeletal and cardiac ryanodine receptors.
Agah R, Kirshenbaum LA, Abdellatif M, et al., 1997, Adenoviral delivery of E2F-1 directs cell cycle reentry and p53-independent apoptosis in postmitotic adult myocardium in vivo., J Clin Invest, Vol: 100, Pages: 2722-2728, ISSN: 0021-9738
Irreversible exit from the cell cycle precludes the ability of cardiac muscle cells to increase cell number after infarction. Using adenoviral E1A, we previously demonstrated dual pocket protein- and p300-dependent pathways in neonatal rat cardiac myocytes, and have proven that E2F-1, which occupies the Rb pocket, suffices for these actions of E1A. By contrast, the susceptibility of adult ventricular cells to viral delivery of exogenous cell cycle regulators has not been tested, in vitro or in vivo. In cultured adult ventricular myocytes, adenoviral gene transfer of E2F-1 induced expression of proliferating cell nuclear antigen, cyclin-dependent protein kinase 4, cell division cycle 2 kinase, DNA synthesis, and apoptosis. In vivo, adenoviral delivery of E2F-1 by direct injection into myocardium induced DNA synthesis, shown by 5'-bromodeoxyuridine incorporation, and accumulation in G2/M, by image analysis of Feulgen-stained nuclei. In p53(-)/- mice, the prevalence of G1 exit was more than twofold greater; however, E2F-1 evoked apoptosis and rapid mortality comparably in both backgrounds. Thus, the differential effects of E2F-1 on G1 exit in wild-type versus p53-deficient mice illustrate the combinatorial power of viral gene delivery to genetically defined recipients: E2F-1 can override the G1/S checkpoint in postmitotic ventricular myocytes in vitro and in vivo, but leads to apoptosis even in p53(-)/- mice.
MacLellan WR, Schneider MD, 1997, Death by design. Programmed cell death in cardiovascular biology and disease., Circ Res, Vol: 81, Pages: 137-144, ISSN: 0009-7330
Programmed cell death (apoptosis) is recognized, increasingly, as a contributing cause of cardiac myocyte loss with ischemia/reperfusion injury, myocardial infarction, and long-standing heart failure. Although the exact mechanisms initiating apoptosis in these in vivo settings remain unproven, insights into the molecular circuitry controlling apoptosis more widely suggest the potential to protect mammalian ventricular muscle from apoptosis through one or more of these pathways, by pharmacological means or, conceivably, gene transfer.
Agah R, Frenkel PA, French BA, et al., 1997, Gene recombination in postmitotic cells. Targeted expression of Cre recombinase provokes cardiac-restricted, site-specific rearrangement in adult ventricular muscle in vivo., J Clin Invest, Vol: 100, Pages: 169-179, ISSN: 0021-9738
Mouse models of human disease can be generated by homologous recombination for germline loss-of-function mutations. However, embryonic-lethal phenotypes and systemic, indirect dysfunction can confound the use of knock-outs to elucidate adult pathophysiology. Site-specific recombination using Cre recombinase can circumvent these pitfalls, in principle, enabling temporal and spatial control of gene recombination. However, direct evidence is lacking for the feasibility of Cre-mediated recombination in postmitotic cells. Here, we exploited transgenic mouse technology plus adenoviral gene transfer to achieve Cre-mediated recombination in cardiac muscle. In vitro, Cre driven by cardiac-specific alpha-myosin heavy chain (alphaMyHC) sequences elicited recombination selectively at loxP sites in purified cardiac myocytes, but not cardiac fibroblasts. In vivo, this alphaMyHC-Cre transgene elicited recombination in cardiac muscle, but not other organs, as ascertained by PCR analysis and localization of a recombination-dependent reporter protein. Adenoviral delivery of Cre in vivo provoked recombination in postmitotic, adult ventricular myocytes. Recombination between loxP sites was not detected in the absence of Cre. These studies demonstrate the feasibility of using Cre-mediated recombination to regulate gene expression in myocardium, with efficient induction of recombination even in terminally differentiated, postmitotic muscle cells. Moreover, delivery of Cre by viral infection provides a simple strategy to control the timing of recombination in myocardium.
Abdellatif M, Schneider MD, 1997, An effector-like function of Ras GTPase-activating protein predominates in cardiac muscle cells., J Biol Chem, Vol: 272, Pages: 525-533, ISSN: 0021-9258
In contrast to familiar role for Ras in proliferation, we and others previously suggested that Ras also mediates hypertrophy, the increase in cell mass characteristic of post-natal ventricular muscle. We showed that activated (G12R) and dominant-negative (S17N) Ha-Ras regulate "constitutive" and growth factor-responsive genes equivalently, in both cardiac myocytes and non-cardiac, Mv1Lu cells. Here, we attempt to delineate pathways by which Ras exerts this global effect. The E63K mutation, which impairs binding of guanine nucleotide releasing factor to Ras, alleviated suppression by S17N, consistent with sequestration of exchange factors as the mechanism for inhibition. To compare potential Ras effector proteins, we first engineered G12R/D38N, to abolish binding of Raf and phosphatidylinositol-3-kinase and established that this site was indispensable for augmenting gene expression. To distinguish between inhibition of Ras by Ras GTPase-activating protein (GAP) versus a potential effector function of GAP, we tested the effector domain substitution P34R: this mutation, which abolishes GAP binding, enhanced Ras-dependent transcription in Mv1Lu cells, yet interfered with Ras-dependent expression in ventricular myocytes. To examine the dichotomous role of Ras-GAP predicted from these P34R results, we transfected both cell types with full-length GAP, the C-terminal catalytic domain (cGAP), or N-terminal Src homology domains (nGAP). In Mv1Lu cells, cGAP markedly inhibited both reporter genes, whereas GAP and nGAP had little effect. Antithetically, in ventricular myocytes, GAP and nGAP activated gene expression, whereas cGAP was ineffective. Thus, Ras activates gene expression through differing effectors contingent on cell type, and an effector-like function of GAP predominates in ventricular muscle.
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