ANKRD1

CARP, also known as Cardiac adriamycin-responsive protein or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene. CARP is highly expressed in cardiac and skeletal muscle, and is a transcription factor involved in development and under conditions of stress. CARP has been implicated in several diseases, including dilated cardiomyopathy, hypertrophic cardiomyopathy, and several skeletal muscle myopathies.27063107765ENSG00000148677ENSMUSG00000024803Q15327Q9CR42NM_014391NM_013468NP_055206NP_038496Human CARP is a 36.2kDa protein composed of 319 amino acids., though in 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 skeletal muscle, suggesting alternate bioactive forms of CARP exist. CARP has been localized to nuclei and Z-discs in animal and human myocytes, and at intercalated discs in human cells.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 cardiomyocytes is regulated by alpha-adrenergic signaling, in part via the transcription factor GATA4. An additional study showed that beta-adrenergic signaling via 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. CARP has a relatively short half-life being longer in cardiomyocytes than endothelial cells; and CARP is degraded by the 26S proteasome via a PEST degron.A wide spectrum of clinical features have been associated with ANKRD1/CARP. Mutations in ANKRD1 have been associated with dilated cardiomyopathy, two of which result in altered binding with TLN1 and FHL2. Mutations in ANKRD1 have also been associated with hypertrophic cardiomyopathy, and have shown to increase binding of CARP to Titin and MYPN. Examination of the functional effects of CARP 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 sarcomeres, an effect that was remedied upon proteasome inhibition via epoxomicin.ANKRD1 has been shown to interact with: