Novel actions of cardiac ankyrin repeat protein

2007 ◽  
Vol 1302 ◽  
pp. 53-64 ◽  
Author(s):  
Susan E. Samaras ◽  
Yubin Shi ◽  
Jeffrey M. Davidson
Keyword(s):  
Ankyrin Repeat ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Cardiac Ankyrin Repeat Protein

CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway

Development ◽  
1997 ◽  
Vol 124 (4) ◽  
pp. 793-804 ◽  
Author(s):  
Y. Zou ◽  
S. Evans ◽  
J. Chen ◽  
H.C. Kuo ◽  
R.P. Harvey ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Myocytes ◽  
Light Chain ◽  
Myosin Light Chain ◽  
Homeobox Gene ◽  
Ankyrin Repeat ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Myosin Light Chain 2 ◽  
Cardiac Ankyrin Repeat Protein

To identify the molecular pathways that guide cardiac ventricular chamber specification, maturation and morphogenesis, we have sought to characterize factors that regulate the expression of the ventricular myosin light chain-2 gene, one of the earliest markers of ventricular regionalization during mammalian cardiogenesis. Previously, our laboratory identified a 28 bp HF-la/MEF-2 element in the MLC-2v promoter region, which confers cardiac ventricular chamber-specific gene expression during murine cardiogenesis, and showed that the ubiquitous transcription factor YB-1 binds to the HF-la site in conjunction with a co-factor. In a search for interacting co-factors, a nuclear ankyrin-like repeat protein CARP (cardiac ankyrin repeat protein) was isolated from a rat neonatal heart cDNA library by yeast two-hybrid screening, using YB-1 as the bait. Co-immunoprecipitation and GST-CARP pulldown studies reveal that CARP forms a physical complex with YB-1 in cardiac myocytes and immunostaining shows that endogenous CARP is localized in the cardiac myocyte nucleus. Co-transfection assays indicate that CARP can negatively regulate an HF-1-TK minimal promoter in an HF-1 sequence-dependent manner in cardiac myocytes, and CARP displays a transcriptional inhibitory activity when fused to a GAL4 DNA-binding domain in both cardiac and noncardiac cell context. Northern analysis revealed that carp mRNA is highly enriched in the adult heart, with only trace levels in skeletal muscle. During murine embryogenesis, endogenous carp expression was first clearly detected as early as E8.5 specifically in heart and is regulated temporally and spatially in the myocardium. Nkx2-5, the murine homologue of Drosophila gene tinman was previously shown to be required for heart tube looping morphogenesis and ventricular chamber-specific myosin light chain-2 expression during mammalian heart development. In Nkx2-5(−/−)embryos, carp expression was found to be significantly and selectively reduced as assessed by both whole-mount in situ hybridizations and RNase protection assays, suggesting that carp is downstream of the homeobox gene Nkx2-5 in the cardiac regulatory network. Co-transfection assays using a dominant negative mutant Nkx2-5 construct with CARP promoter-luciferase reporter constructs in cardiac myocytes confirms that Nkx2-5 either directly or indirectly regulates carp at the transcriptional level. Finally, a carp promoter-lacZ transgene, which displays cardiac-specific expression in wild-type and Nkx2-5(+/−) background, was also significantly reduced in Nkx2-5(−/−) embryos, indicating that Nkx2-5 either directly or indirectly regulates carp promoter activity during in vivo cardiogenesis as well as in cultured cardiac myocytes. Thus, CARP is a YB-1 associated factor and represents the first identified cardiac-restricted downstream regulatory gene in the homeobox gene Nkx2-5 pathway and may serve as a negative regulator of HF-1-dependent pathways for ventricular muscle gene expression.

α1-Adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes

Gene ◽  
2002 ◽  
Vol 297 (1-2) ◽  
pp. 1-9 ◽  
Author(s):  
Tomoji Maeda ◽  
Jorge Sepulveda ◽  
Hsiao-Huei Chen ◽  
Alexandre F.R. Stewart
Keyword(s):  
Cardiac Myocytes ◽  
Protein Gene ◽  
Ankyrin Repeat ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Cardiac Ankyrin Repeat Protein ◽  
Adrenergic Activation

scholarly journals The Cardiac Ankyrin Repeat Protein (ANKRD1) Is Associated With Proteins Of The Cytoskeleton

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
Marian Naguib ◽  
Daniel Min‐Seok Kwak ◽  
Michael Reinartz ◽  
Barbara Kurig ◽  
Stephan Weser ◽  
...  
Keyword(s):  
Ankyrin Repeat ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Cardiac Ankyrin Repeat Protein

Abstract 308: Targeted Inhibition of Cardiac Ankyrin Repeat Protein Disrupts Sarcomeric ERK-GATA4 Signaling at the Titin I-band and Abrogates Agonist-Induced Cardiac Hypertrophy

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chee Lim ◽  
Lin Zhong ◽  
Manuel Chiusa ◽  
Adrian Cadar ◽  
Susan Samaras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Dna Binding ◽  
Regulatory Protein ◽  
Ankyrin Repeat ◽  
Mitogen Activated Protein Kinase ◽  
Repeat Protein ◽  
Hypertrophic Response ◽  
Ankyrin Repeat Protein ◽  
Cardiac Ankyrin Repeat Protein

Hypertrophic cardiomyocyte growth occurs in response to various stress stimuli including biomechanical stress and neurohormonal factors. Accumulating evidence suggest that sarcomere signaling complexes play a pivotal role in the cardiomyocyte hypertrophic response by transmitting signals to the nucleus to induce gene expression. Cardiac ankyrin repeat protein (CARP, Ankrd1) is a transcriptional regulatory protein that also associates with the titin I-band spring domain, however the exact role of CARP in the heart remains to be elucidated. We report that CARP directly interacts with mitogen activated protein kinase ERK1/2 and cardiac transcription factor GATA4. Phenylephrine (PE) stimulation in cardiomyocytes induced ERK1/2 and GATA4 to transiently co-localize with sarcomeric CARP, followed by translocation of CARP and GATA4 to the nucleus. Four-and-a-half-LIM (FHL) domains proteins are part of a sarcomeric ERK2 sensory complex and knockdown of CARP by small interfering RNA (siRNA) resulted in disruption of FHL1 and FHL2. Moreover, loss of CARP attenuated PE-induced phosphorylation of ERK1/2 and GATA4, decreased GATA4 DNA binding, and prevented PE-induced cardiomyocyte growth. Mice lacking CARP have decreased FHL1 levels, and PE stimulation in wild-type mice resulted in elevated GATA4 phosphorylation and a hypertrophic response, which were completely abrogated in CARP-KO mice. We demonstrate that CARP plays an important role in PE-induced hypertrophic signaling by recruiting ERK2 and GATA4 into a titin I-band macro-molecular complex to induce GATA4 activation, followed by translocation of CARP and GATA4 to the nucleus to enhance GATA4 DNA binding and hypertrophic gene expression. Loss of CARP destabilizes FHL1 and FHL2, resulting in disruption of the PE-induced sarcomeric complex and abrogation of the cardiomyocyte hypertrophic response. These data reveal a novel role for sarcomeric titin I-band as a transcription factor activation hub that induces downstream nuclear signaling in response to agonist-induced hypertrophic stimuli.

scholarly journals Cardiac Ankyrin Repeat Protein Gene (ANKRD1) Mutations in Hypertrophic Cardiomyopathy

2009 ◽  
Vol 54 (4) ◽  
pp. 334-342 ◽  
Author(s):  
Takuro Arimura ◽  
J. Martijn Bos ◽  
Akinori Sato ◽  
Toru Kubo ◽  
Hiroshi Okamoto ◽  
...  
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Protein Gene ◽  
Ankyrin Repeat ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Cardiac Ankyrin Repeat Protein

scholarly journals Characterization of muscle ankyrin repeat proteins in human skeletal muscle

2017 ◽  
Vol 313 (3) ◽  
pp. C327-C339 ◽  
Author(s):  
Stefan G. Wette ◽  
Heather K. Smith ◽  
Graham D. Lamb ◽  
Robyn M. Murphy
Keyword(s):  
Skeletal Muscle ◽  
Human Skeletal Muscle ◽  
Ankyrin Repeat ◽  
Absolute Amount ◽  
Repeat Protein ◽  
Ankyrin Repeat Protein ◽  
Repeat Proteins ◽  
Cardiac Ankyrin Repeat Protein ◽  
Repeat Domain ◽  
Ankyrin Repeat Proteins

Muscle ankyrin repeat proteins (MARPs) are a family of titin-associated, stress-response molecules and putative transducers of stretch-induced signaling in skeletal muscle. In cardiac muscle, cardiac ankyrin repeat protein (CARP) and diabetes-related ankyrin repeat protein (DARP) reportedly redistribute from binding sites on titin to the nucleus following a prolonged stretch. However, it is unclear whether ankyrin repeat domain protein 2 (Ankrd 2) shows comparable stretch-induced redistribution to the nucleus. We measured the following in rested human skeletal muscle: 1) the absolute amount of MARPs and 2) the distribution of Ankrd 2 and DARP in both single fibers and whole muscle preparations. In absolute amounts, Ankrd 2 is the most abundant MARP in human skeletal muscle, there being ~3.1 µmol/kg, much greater than DARP and CARP (~0.11 and ~0.02 µmol/kg, respectively). All DARP was found to be tightly bound at cytoskeletal (or possibly nuclear) sites. In contrast, ~70% of the total Ankrd 2 is freely diffusible in the cytosol [including virtually all of the phosphorylated (p)Ankrd 2-Ser99 form], ~15% is bound to non-nuclear membranes, and ~15% is bound at cytoskeletal sites, likely at the N2A region of titin. These data are not consistent with the proposal that Ankrd 2, per se, or pAnkrd 2-Ser99 mediates stretch-induced signaling in skeletal muscle, dissociating from titin and translocating to the nucleus, because the majority of these forms of Ankrd 2 are already free in the cytosol. It will be necessary to show that the titin-associated Ankrd 2 is modified by stretch in some as-yet-unidentified way, distinct from the diffusible pool, if it is to act as a stretch-sensitive signaling molecule.

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