ANKRD1

CARP, also known as Cardiac adriamycin-responsive protein or Cardiac ankyrin repeat protein is a is_associated_with::protein that in humans is encoded by the ANKRD1 is_associated_with::gene. CARP is highly expressed in cardiac and is_associated_with::skeletal muscle, and is a is_associated_with::transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including is_associated_with::dilated cardiomyopathy, is_associated_with::hypertrophic cardiomyopathy, and several skeletal muscle myopathies.

Structure
Human CARP is a 36.2kDa protein composed of 319 amino acids., though in is_associated_with::cardiomyocytes, CARP can exist as multiple alternatively spliced forms. CARP contains five tandem ankyrin repeats. Studies have shown that CARP can homodimerize. Studies have also shown that CARP is N-terminally, post-translationally cleaved by calpain-3 in is_associated_with::skeletal muscle, suggesting alternate bioactive forms of CARP exist. CARP has been localized to nuclei and Z-discs in animal and human is_associated_with::myocytes, and at is_associated_with::intercalated discs in human cells.

Function
CARP was originally identified as a YB-1-associating, cardiac-restricted transcription co-repressor in the homeobox NKX2-5 pathway that is involved in cardiac ventricular chamber specification, maturation and morphogenesis, and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent  as well as M-CAT cis-element-dependent mechanism. Subsequent studies showed that CARP expression in is_associated_with::cardiomyocytes is regulated by alpha-adrenergic signaling, in part via the transcription factor GATA4. An additional study showed that beta-adrenergic signaling via is_associated_with::protein kinase A and CaM kinase induces the expression of CARP, and that CARP may have a negative effect on contractile function. CARP has also been identified as a transcriptional co-activator of tumor suppressor protein p53 for stimulating gene expression in muscle; p53 was found to be an upstream effector of CARP via upregulation of the proximal ANKRD1 promoter. Interestingly, CARP protein has a relatively short half-life being longer in is_associated_with::cardiomyocytes than is_associated_with::endothelial cells; and CARP is degraded by the 26S proteasome via a PEST degron.

In animal models of disease and injury, CARP has been characterized to be a stress-inducible is_associated_with::myofibrillar protein. CARP has been shown to play a role in is_associated_with::skeletal muscle structure remodeling, and repair, being expressed in is_associated_with::skeletal muscle near myotendinous junctions, and in vascular smooth muscle cells, as a downstream target of TGF-beta/Smad sigmaling in response to balloon injury and atherosclerotic plaques. Further studies have identified a role for CARP in initiation and regulation of is_associated_with::arteriogenesis. Decreased expression of CARP in cardiac cells within the ischemic region was detected in a rat model of is_associated_with::ischemic injury, and was thought to be linked to the induction of GADD153, an is_associated_with::apoptosis-related gene. In is_associated_with::cardiomyocytes treated with is_associated_with::doxorubicin, a model of is_associated_with::anthracycline-induced is_associated_with::cardiomyopathy, CARP is_associated_with::mRNA and is_associated_with::protein levels were depleted, is_associated_with::myofilament is_associated_with::gene transcription was attenuated and is_associated_with::sarcomeres showed significant disarray.

In a transgenic mouse model of cardiac-specific overexpression of CARP, mice exhibited normal physiology at baseline, but were protected against pathological is_associated_with::cardiac hypertrophy induced via pressure-overload or is_associated_with::isoproterenol, which could be attributed to the downregulation of the ERK1/2, MEK and TGFbeta-1 pathways. Another study demonstrated that adenoviral overexpression of CARP in is_associated_with::cardiomyocytes enhances is_associated_with::cardiac hypertrophy induced by is_associated_with::Angiotensin II or pressure-overload and promotoes is_associated_with::cardiomyocyte is_associated_with::apoptosis via p53 activation and is_associated_with::mitochondrial dysfunction. However, transgenic knockout models of either CARP alone or CARP in combination with the other muscle ankyrin repeat proteins (MARPs), is_associated_with::ANKRD2 and is_associated_with::ANKRD23 demonstrated a lack of cardiac phenotype; mice displayed normal cardiac function at baseline and in response to pressure overload-induced is_associated_with::cardiac hypertrophy, suggesting that these proteins are not essential.

Interactions between CARP and the sarcomeric proteins myopalladin and is_associated_with::titin suggest that it may also be involved in the myofibrillar stretch-sensor system. Passive stretch in fetal is_associated_with::cardiomyocytes induced differential CARP distribution at nuclei and I-band is_associated_with::titin N2A regions. In a mouse model of is_associated_with::muscular dystrophy with is_associated_with::myositis (mdm) caused by a small deletion in is_associated_with::titin, CARP is_associated_with::mRNA expression was shown to be 30-fold elevated in is_associated_with::skeletal muscle tissue.

Clinical significance
A wide spectrum of clinical features have been associated with ANKRD1/CARP is_associated_with::protein. Mutations in ANKRD1 have been associated with is_associated_with::dilated cardiomyopathy, two of which result in altered binding with is_associated_with::TLN1 and is_associated_with::FHL2. Mutations in ANKRD1 have also been associated with is_associated_with::hypertrophic cardiomyopathy, and have shown to increase binding of CARP to is_associated_with::Titin and is_associated_with::MYPN. Examination of the functional effects of CARP is_associated_with::hypertrophic cardiomyopathy mutations in engineered heart tissue demonstrated that Thr123Met was a gain-of-function mutation exhibiting augmented contractile properties; whereas Pro52Ala and Ile280Val were unstable and failed to incorporate into is_associated_with::sarcomeres, an effect that was remedied upon proteasome inhibition via is_associated_with::epoxomicin.

A missense mutation in ANKRD1 was shown to be associated with the congenital heart defect, is_associated_with::Anomalous pulmonary venous connection. CARP has been found as a sensitive and specific biomarker for the differential diagnosis of is_associated_with::rhabdomyosarcoma. Interstingly, ANKRD1 is_associated_with::mRNA levels correlate with patient platinum sensitivity, thus ANKRD1 associates with platinum-based is_associated_with::chemotherapy treatment outcome in ovarian adenocarcinoma patients.

CARP is_associated_with::protein and is_associated_with::mRNA expression has been shown to be upregulated in left is_associated_with::ventricles of is_associated_with::heart failure patients. Studies in patients with is_associated_with::amyotrophic lateral sclerosis, is_associated_with::spinal muscular atrophy, and is_associated_with::congenital myopathy, also found altered expression of CARP in is_associated_with::skeletal muscle fibers. Another study in is_associated_with::congenital muscular dystrophy and is_associated_with::Duchenne muscular dystrophy patients showed elevated expression of CARP. CARP expression is also elevated in patients with is_associated_with::lupus nephritis, and associates with is_associated_with::proteinuria severity, suggesting that it may have biomarker potential.

Interactions
ANKRD1 has been shown to interact with:


 * is_associated_with::Titin,
 * is_associated_with::MYPN,
 * is_associated_with::YBX1,
 * is_associated_with::CASQ2,
 * is_associated_with::DES,
 * is_associated_with::TP53,
 * is_associated_with::TLN1, and
 * is_associated_with::FHL2.