Biology:ANKRD1

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


Ankyrin repeat domain-containing protein 1, or Cardiac ankyrin repeat protein is a protein that in humans is encoded by the ANKRD1 gene also known as CARP.[1][2][3] 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.

Structure

Human cardiac ankyrin repeat protein is a 36.2kDa protein composed of 319 amino acids.,[4] though in cardiomyocytes, CARP can exist as multiple alternatively spliced forms.[5] CARP contains five tandem ankyrin repeats. Studies have shown that CARP can homodimerize.[6] 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.[7] CARP has been localized to nuclei and Z-discs in animal and human muscle cells, and at intercalated discs in human cardiac muscle cells. [8]

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,[9][10][11] and whose mRNA levels are exquisitely sensitive to Doxorubicin, mediated through a hydrogen peroxide/ERK/p38MAP kinase-dependent[12][13] as well as M-CAT cis-element-dependent[14] mechanism. Subsequent studies showed that CARP expression in cardiomyocytes is regulated by alpha-adrenergic signaling, in part via the transcription factor GATA4.[15][16] 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.[17] 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.[18] 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.[19][20]

In animal models of disease and injury, CARP has been characterized to be a stress-inducible myofibrillar protein. CARP has been shown to play a role in skeletal muscle structure[21] remodeling,[22] and repair, being expressed in skeletal muscle near myotendinous junctions,[23] and in vascular smooth muscle cells, as a downstream target of TGF-beta/Smad sigmaling in response to balloon injury[24] and atherosclerotic plaques.[25] Further studies have identified a role for CARP in initiation and regulation of arteriogenesis.[26][27][28] Decreased expression of CARP in cardiac cells within the ischemic region was detected in a rat model of ischemic injury, and was thought to be linked to the induction of GADD153, an apoptosis-related gene.[29] In cardiomyocytes treated with doxorubicin, a model of anthracycline-induced cardiomyopathy, CARP mRNA and protein levels were depleted, myofilament gene transcription was attenuated and sarcomeres showed significant disarray.[30]

In a transgenic mouse model of cardiac-specific overexpression of CARP, mice exhibited normal physiology at baseline, but were protected against pathological cardiac hypertrophy induced via pressure-overload or isoproterenol, which could be attributed to the downregulation of the ERK1/2, MEK and TGFbeta-1 pathways.[31] Another study demonstrated that adenoviral overexpression of CARP in cardiomyocytes enhances cardiac hypertrophy induced by Angiotensin II or pressure-overload[32] and promotes cardiomyocyte apoptosis via p53 activation and mitochondrial dysfunction.[33] However, transgenic knockout models of either CARP alone or CARP in combination with the other muscle ankyrin repeat proteins (MARPs), ANKRD2 and ANKRD23 demonstrated a lack of cardiac phenotype; mice displayed normal cardiac function at baseline and in response to pressure overload-induced cardiac hypertrophy, suggesting that these proteins are not essential.[34]

Interactions between CARP and the sarcomeric proteins myopalladin and titin suggest that it may also be involved in the myofibrillar stretch-sensor system. Passive stretch in fetal cardiomyocytes induced differential CARP distribution at nuclei and I-band titin N2A regions.[35] In a mouse model of muscular dystrophy with myositis (mdm) caused by a small deletion in titin, CARP mRNA expression was shown to be 30-fold elevated in skeletal muscle tissue.[36]

Clinical significance

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.[37][38] Mutations in ANKRD1 have also been associated with hypertrophic cardiomyopathy, and have shown to increase binding of CARP to Titin and MYPN.[39] 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.[40]

A missense mutation in ANKRD1 was shown to be associated with the congenital heart defect, Anomalous pulmonary venous connection.[41] CARP has been found as a sensitive and specific biomarker for the differential diagnosis of rhabdomyosarcoma.[42] ANKRD1 mRNA levels correlate with patient platinum sensitivity, thus ANKRD1 associates with platinum-based chemotherapy treatment outcome in ovarian adenocarcinoma patients.[43]

CARP and mRNA expression has been shown to be upregulated in left ventricles of heart failure patients.[44][45][46][47] Studies in patients with amyotrophic lateral sclerosis,[48] spinal muscular atrophy, and congenital myopathy,[49] also found altered expression of CARP in skeletal muscle fibers. Another study in congenital muscular dystrophy and Duchenne muscular dystrophy patients showed elevated expression of CARP.[50] CARP expression is also elevated in patients with lupus nephritis, and associates with proteinuria severity, suggesting that it may have biomarker potential.[51]

Interactions

ANKRD1 has been shown to interact with:


References

  1. ↑ "UniProt". https://beta.uniprot.org/uniprotkb/Q15327/entry. 
  2. ↑ "Identification and characterization of a novel cytokine-inducible nuclear protein from human endothelial cells". J. Biol. Chem. 270 (17): 10236–45. June 1995. doi:10.1074/jbc.270.17.10236. PMID 7730328. 
  3. ↑ "Entrez Gene: ANKRD1 ankyrin repeat domain 1 (cardiac muscle)". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=27063. 
  4. ↑ "Protein sequence of human ANKRD1 (Uniprot ID: Q15327)". http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=Q15327. 
  5. ↑ "Intron retention generates ANKRD1 splice variants that are co-regulated with the main transcript in normal and failing myocardium". Gene 440 (1–2): 28–41. Jul 2009. doi:10.1016/j.gene.2009.03.017. PMID 19341785. 
  6. ↑ 6.0 6.1 "Dimerization of the cardiac ankyrin protein CARP: implications for MARP titin-based signaling". Journal of Muscle Research and Cell Motility 26 (6–8): 401–8. 2005. doi:10.1007/s10974-005-9022-9. PMID 16450059. 
  7. ↑ "A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-κB pathway in skeletal muscle". The FEBS Journal 277 (20): 4322–37. Oct 2010. doi:10.1111/j.1742-4658.2010.07820.x. PMID 20860623. 
  8. ↑ "Profiling of skeletal muscle Ankrd2 protein in human cardiac tissue and neonatal rat cardiomyocytes". Histochemistry and Cell Biology 143 (6): 583–97. Jun 2015. doi:10.1007/s00418-015-1307-5. PMID 25585647. 
  9. ↑ 9.0 9.1 "CARP, a cardiac ankyrin repeat protein, is downstream in the Nkx2-5 homeobox gene pathway". Development 124 (4): 793–804. Feb 1997. doi:10.1242/dev.124.4.793. PMID 9043061. 
  10. ↑ "Control of segmental expression of the cardiac-restricted ankyrin repeat protein gene by distinct regulatory pathways in murine cardiogenesis". Development 126 (19): 4223–34. Oct 1999. doi:10.1242/dev.126.19.4223. PMID 10477291. 
  11. ↑ "Up-regulation of natriuretic peptides in the ventricle of Csx/Nkx2-5 transgenic mice". Biochemical and Biophysical Research Communications 270 (3): 1074–9. Apr 2000. doi:10.1006/bbrc.2000.2561. PMID 10772952. 
  12. ↑ "A novel cardiac-restricted target for doxorubicin. CARP, a nuclear modulator of gene expression in cardiac progenitor cells and cardiomyocytes". The Journal of Biological Chemistry 272 (36): 22800–8. Sep 1997. doi:10.1074/jbc.272.36.22800. PMID 9278441. 
  13. ↑ "Doxorubicin represses CARP gene transcription through the generation of oxidative stress in neonatal rat cardiac myocytes: possible role of serine/threonine kinase-dependent pathways". Journal of Molecular and Cellular Cardiology 32 (8): 1401–14. Aug 2000. doi:10.1006/jmcc.2000.1173. PMID 10900167. 
  14. ↑ "Cardiac ankyrin repeat protein is a novel marker of cardiac hypertrophy: role of M-CAT element within the promoter". Hypertension 36 (1): 48–53. Jul 2000. doi:10.1161/01.hyp.36.1.48. PMID 10904011. 
  15. ↑ "Alpha(1)-adrenergic activation of the cardiac ankyrin repeat protein gene in cardiac myocytes". Gene 297 (1–2): 1–9. Sep 2002. doi:10.1016/s0378-1119(02)00924-1. PMID 12384280. 
  16. ↑ "Targeted inhibition of ANKRD1 disrupts sarcomeric ERK-GATA4 signal transduction and abrogates phenylephrine-induced cardiomyocyte hypertrophy". Cardiovascular Research 106 (2): 261–71. May 2015. doi:10.1093/cvr/cvv108. PMID 25770146. 
  17. ↑ "Beta-adrenergic stimulation induces cardiac ankyrin repeat protein expression: involvement of protein kinase A and calmodulin-dependent kinase". Cardiovascular Research 59 (3): 563–72. Sep 2003. doi:10.1016/s0008-6363(03)00476-0. PMID 14499857. 
  18. ↑ 18.0 18.1 "A novel role for cardiac ankyrin repeat protein Ankrd1/CARP as a co-activator of the p53 tumor suppressor protein". Archives of Biochemistry and Biophysics 502 (1): 60–7. Oct 2010. doi:10.1016/j.abb.2010.06.029. PMID 20599664. 
  19. ↑ "26S proteasome regulation of Ankrd1/CARP in adult rat ventricular myocytes and human microvascular endothelial cells". Biochemical and Biophysical Research Communications 425 (4): 830–5. Sep 2012. doi:10.1016/j.bbrc.2012.07.162. PMID 22892129. 
  20. ↑ "Intracellular ANKRD1 protein levels are regulated by 26S proteasome-mediated degradation". FEBS Letters 583 (15): 2486–92. Aug 2009. doi:10.1016/j.febslet.2009.07.001. PMID 19589340. 
  21. ↑ "Structural and regulatory roles of muscle ankyrin repeat protein family in skeletal muscle". American Journal of Physiology. Cell Physiology 293 (1): C218–27. Jul 2007. doi:10.1152/ajpcell.00055.2007. PMID 17392382. 
  22. ↑ "Cardiac ankyrin repeat protein is a marker of skeletal muscle pathological remodelling". The FEBS Journal 276 (3): 669–84. Feb 2009. doi:10.1111/j.1742-4658.2008.06814.x. PMID 19143834. 
  23. ↑ "Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis". The Journal of Cell Biology 139 (5): 1231–42. Dec 1997. doi:10.1083/jcb.139.5.1231. PMID 9382869. 
  24. ↑ "Transforming growth factor-beta/Smads signaling induces transcription of the cell type-restricted ankyrin repeat protein CARP gene through CAGA motif in vascular smooth muscle cells". Circulation Research 88 (1): 30–6. Jan 2001. doi:10.1161/01.res.88.1.30. PMID 11139470. 
  25. ↑ "Cardiac ankyrin repeat protein (CARP) expression in human and murine atherosclerotic lesions: activin induces CARP in smooth muscle cells". Arteriosclerosis, Thrombosis, and Vascular Biology 23 (1): 64–8. Jan 2003. doi:10.1161/01.atv.0000042218.13101.50. PMID 12524226. 
  26. ↑ "Arteriogenesis is associated with an induction of the cardiac ankyrin repeat protein (carp)". Cardiovascular Research 59 (3): 573–81. Sep 2003. doi:10.1016/s0008-6363(03)00511-x. PMID 14499858. 
  27. ↑ "CARP, a cardiac ankyrin repeat protein, is up-regulated during wound healing and induces angiogenesis in experimental granulation tissue". The American Journal of Pathology 166 (1): 303–12. Jan 2005. doi:10.1016/S0002-9440(10)62254-7. PMID 15632022. 
  28. ↑ "CARP: fishing for novel mechanisms of neovascularization". The Journal of Investigative Dermatology. Symposium Proceedings 11 (1): 124–31. Sep 2006. doi:10.1038/sj.jidsymp.5650014. PMID 17069020. 
  29. ↑ "Involvement of GADD153 and cardiac ankyrin repeat protein in cardiac ischemia-reperfusion injury". Experimental & Molecular Medicine 41 (4): 243–52. Apr 2009. doi:10.3858/emm.2009.41.4.027. PMID 19299913. 
  30. ↑ "Disruption of a GATA4/Ankrd1 signaling axis in cardiomyocytes leads to sarcomere disarray: implications for anthracycline cardiomyopathy". PLOS ONE 7 (4): e35743. 2012. doi:10.1371/journal.pone.0035743. PMID 22532871. Bibcode: 2012PLoSO...735743C. 
  31. ↑ "Cardiac ankyrin repeat protein attenuates cardiac hypertrophy by inhibition of ERK1/2 and TGF-β signaling pathways". PLOS ONE 7 (12): e50436. 2012. doi:10.1371/journal.pone.0050436. PMID 23227174. Bibcode: 2012PLoSO...750436S. 
  32. ↑ "Cytosolic CARP promotes angiotensin II- or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation". PLOS ONE 9 (8): e104040. 2014. doi:10.1371/journal.pone.0104040. PMID 25089522. Bibcode: 2014PLoSO...9j4040C. 
  33. ↑ "Overexpression of ankyrin repeat domain 1 enhances cardiomyocyte apoptosis by promoting p53 activation and mitochondrial dysfunction in rodents". Clinical Science 128 (10): 665–78. May 2015. doi:10.1042/CS20140586. PMID 25511237. 
  34. ↑ "The muscle ankyrin repeat proteins CARP, Ankrd2, and DARP are not essential for normal cardiac development and function at basal conditions and in response to pressure overload". PLOS ONE 9 (4): e93638. 2014. doi:10.1371/journal.pone.0093638. PMID 24736439. Bibcode: 2014PLoSO...993638B. 
  35. ↑ "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". Journal of Molecular Biology 333 (5): 951–64. Nov 2003. doi:10.1016/j.jmb.2003.09.012. PMID 14583192. 
  36. ↑ "Induction and myofibrillar targeting of CARP, and suppression of the Nkx2.5 pathway in the MDM mouse with impaired titin-based signaling". Journal of Molecular Biology 336 (1): 145–54. Feb 2004. doi:10.1016/j.jmb.2003.12.021. PMID 14741210. 
  37. ↑ 37.0 37.1 37.2 "ANKRD1, the gene encoding cardiac ankyrin repeat protein, is a novel dilated cardiomyopathy gene". Journal of the American College of Cardiology 54 (4): 325–33. Jul 2009. doi:10.1016/j.jacc.2009.02.076. PMID 19608030. 
  38. ↑ "Mutations in the ANKRD1 gene encoding CARP are responsible for human dilated cardiomyopathy". European Heart Journal 30 (17): 2128–36. Sep 2009. doi:10.1093/eurheartj/ehp225. PMID 19525294. 
  39. ↑ "Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy". Journal of the American College of Cardiology 54 (4): 334–42. Jul 2009. doi:10.1016/j.jacc.2008.12.082. PMID 19608031. 
  40. ↑ "Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue". Basic Research in Cardiology 108 (3): 349. May 2013. doi:10.1007/s00395-013-0349-x. PMID 23572067. 
  41. ↑ "Transcriptional deregulation and a missense mutation define ANKRD1 as a candidate gene for total anomalous pulmonary venous return". Human Mutation 29 (4): 468–74. Apr 2008. doi:10.1002/humu.20711. PMID 18273862. 
  42. ↑ "Expression of cardiac ankyrin repeat protein, CARP, in malignant tumors: diagnostic use of CARP protein immunostaining in rhabdomyosarcoma". Human Pathology 39 (11): 1673–9. Nov 2008. doi:10.1016/j.humpath.2008.04.009. PMID 18656235. 
  43. ↑ "Ankyrin repeat domain 1, ANKRD1, a novel determinant of cisplatin sensitivity expressed in ovarian cancer". Clinical Cancer Research 14 (21): 6924–32. Nov 2008. doi:10.1158/1078-0432.CCR-07-5189. PMID 18980987. 
  44. ↑ "Induction of ankrd1 in dilated cardiomyopathy correlates with the heart failure progression". BioMed Research International 2015: 273936. 2015. doi:10.1155/2015/273936. PMID 25961010. 
  45. ↑ "Upregulated expression of cardiac ankyrin repeat protein in human failing hearts due to arrhythmogenic right ventricular cardiomyopathy". European Journal of Heart Failure 11 (6): 559–66. Jun 2009. doi:10.1093/eurjhf/hfp049. PMID 19359327. 
  46. ↑ "Altered titin expression, myocardial stiffness, and left ventricular function in patients with dilated cardiomyopathy". Circulation 110 (2): 155–62. Jul 2004. doi:10.1161/01.CIR.0000135591.37759.AF. PMID 15238456. 
  47. ↑ "Cardiac ankyrin repeat protein, a negative regulator of cardiac gene expression, is augmented in human heart failure". Biochemical and Biophysical Research Communications 293 (5): 1377–82. May 2002. doi:10.1016/S0006-291X(02)00387-X. PMID 12054667. 
  48. ↑ "Altered expression of cardiac ankyrin repeat protein and its homologue, ankyrin repeat protein with PEST and proline-rich region, in atrophic muscles in amyotrophic lateral sclerosis". Pathobiology 70 (4): 197–203. Apr 2003. doi:10.1159/000069329. PMID 12679596. 
  49. ↑ "Cardiac ankyrin repeat protein is preferentially induced in atrophic myofibers of congenital myopathy and spinal muscular atrophy". Pathology International 53 (10): 653–8. Oct 2003. doi:10.1046/j.1440-1827.2003.01541.x. PMID 14516314. 
  50. ↑ "Cardiac-restricted ankyrin-repeated protein is differentially induced in duchenne and congenital muscular dystrophy". Laboratory Investigation 83 (5): 711–9. May 2003. doi:10.1097/01.lab.0000067484.35298.1a. PMID 12746480. 
  51. ↑ "Upregulated expression of cardiac ankyrin-repeated protein in renal podocytes is associated with proteinuria severity in lupus nephritis". Human Pathology 38 (3): 410–9. Mar 2007. doi:10.1016/j.humpath.2006.09.006. PMID 17239933. 
  52. ↑ 52.0 52.1 "The muscle ankyrin repeat proteins: CARP, ankrd2/Arpp and DARP as a family of titin filament-based stress response molecules". J. Mol. Biol. 333 (5): 951–64. November 2003. doi:10.1016/j.jmb.2003.09.012. PMID 14583192. 
  53. ↑ "Myopalladin, a novel 145-kilodalton sarcomeric protein with multiple roles in Z-disc and I-band protein assemblies". J. Cell Biol. 153 (2): 413–27. April 2001. doi:10.1083/jcb.153.2.413. PMID 11309420. 
  54. ↑ "ANKRD1 specifically binds CASQ2 in heart extracts and both proteins are co-enriched in piglet cardiac Purkinje cells". Journal of Molecular and Cellular Cardiology 38 (2): 353–65. Feb 2005. doi:10.1016/j.yjmcc.2004.11.034. PMID 15698842. 

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