Posttranslational control of HuR function

Wiley Interdisciplinary Reviews: RNA

Volumn 8, Issue 1, 2017, Pages

  Grammatikakis, Ioannis ^a   Abdelmohsen, Kotb ^a   Gorospe, Myriam ^a  

^a NATIONAL INSTITUTE ON AGING   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CHECKPOINT KINASE 2; CYCLIN DEPENDENT KINASE; CYCLIN DEPENDENT KINASE 1; CYCLIN DEPENDENT KINASE 2; CYCLIN DEPENDENT KINASE 5; ELAV LIKE PROTEIN 1; EXTRACELLULAR SIGNAL REGULATED KINASE 8; JANUS KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE P38; PROTEASOME; PROTEIN KINASE C; UBIQUITIN PROTEIN LIGASE E3; UNCLASSIFIED DRUG; MESSENGER RNA;

GENE EXPRESSION; HUMAN; MOLECULAR RECOGNITION; NEDDYLATION; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN METHYLATION; PROTEIN MODIFICATION; PROTEIN PHOSPHORYLATION; PROTEIN RNA BINDING; PROTEIN TARGETING; REVIEW; RNA PROCESSING; UBIQUITINATION; ANIMAL; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; PROTEIN PROCESSING;

ANIMALS; ELAV-LIKE PROTEIN 1; GENE EXPRESSION REGULATION; HUMANS; PROTEIN PROCESSING, POST-TRANSLATIONAL; RNA, MESSENGER;

EID: 84995780831     PISSN: 17577004     EISSN: 17577012     Source Type: Journal    
DOI: 10.1002/wrna.1372     Document Type: Review

References (100)

1. Uy R, Wold F. Posttranslational covalent modification of proteins. Science 1977, 198:890–896.
2. Xin F, Radivojac P. Post-translational modifications induce significant yet not extreme changes to protein structure. Bioinformatics 2012, 28:2905–2913.
3. Walsh CT, Garneau-Tsodikova S, Gatto GJ Jr. Protein posttranslational modifications: the chemistry of proteome diversifications. Angew Chem Int Ed Engl 2005, 44:7342–7372.
4. Bode AM, Dong Z. Post-translational modification of p53 in tumorigenesis. Nat Rev Cancer 2004, 4:793–805.
5. Martin L, Latypova X, Terro F. Post-translational modifications of τ protein: implications for Alzheimer's disease. Neurochem Int 2011, 58:458–471.
6. Van Eyk JE. Overview: the maturing of proteomics in cardiovascular research. Circ Res 2011, 108:490–498.
7. Dreyfuss G, Kim VN, Kataoka N. Messenger-RNA-binding proteins and the messages they carry. Nat Rev Mol Cell Biol 2002, 3:195–205.
8. Keene JD. RNA regulons: coordination of post-transcriptional events. Nat Rev Genet 2007, 8:533–543.
9. Moore MJ. From birth to death: the complex lives of eukaryotic mRNAs. Science 2005, 309:1514–1518.
10. Hinman MN, Lou H. Diverse molecular functions of Hu proteins. Cell Mol Life Sci 2008, 65:3168–3181.
11. Simone LE, Keene JD. Mechanisms coordinating ELAV/Hu mRNA regulons. Curr Opin Genet Dev 2013, 23:35–43.
12. Doller A, Akool e-S, Huwiler A, Müller R, Radeke HH, Pfeilschifter J, Eberhardt W. Posttranslational modification of the AU-rich element binding protein HuR by protein kinase Cδ elicits angiotensin II-induced stabilization and nuclear export of cyclooxygenase 2 mRNA. Mol Cell Biol 2008, 28:2608–2625.
13. Gallouzi IE, Steitz JA. Delineation of mRNA export pathways by the use of cell-permeable peptides. Science 2001, 294:1895–1901.
14. Prechtel AT, Chemnitz J, Schirmer S, Ehlers C, Langbein-Detsch I, Stülke J, Dabauvalle MC, Kehlenbach RH, Hauber J. Expression of CD83 is regulated by HuR via a novel cis-active coding region RNA element. J Biol Chem 2006, 281:10912–10925.
15. Yi J, Chang N, Liu X, Guo G, Xue L, Tong T, Gorospe M, Wang W. Reduced nuclear export of HuR mRNA by HuR is linked to the loss of HuR in replicative senescence. Nucleic Acids Res 2010, 38:1547–1558.
16. Abdelmohsen K, Kuwano Y, Kim HH, Gorospe M. Posttranscriptional gene regulation by RNA-binding proteins during oxidative stress: implications for cellular senescence. Biol Chem 2008, 389:243–255.
17. Mukherjee N, Corcoran DL, Nusbaum JD, Reid DW, Georgiev S, Hafner M, Ascano M Jr, Tuschl T, Ohler U, Keene JD. Integrative regulatory mapping indicates that the RNA-binding protein HuR couples pre-mRNA processing and mRNA stability. Mol Cell 2011, 43:327–339.
18. Lebedeva S, Jens M, Theil K, Schwanhausser B, Selbach M, Landthaler M, Rajewsky N. Transcriptome-wide analysis of regulatory interactions of the RNA-binding protein HuR. Mol Cell 2011, 43:340–352.
19. Abdelmohsen K, Gorospe M. Posttranscriptional regulation of cancer traits by HuR. Wiley Interdiscip Rev RNA 2010, 1:214–229.
20. Figueroa A, Cuadrado A, Fan J, Atasoy U, Muscat GE, Munoz-Canoves P, Gorospe M, Munoz A. Role of HuR in skeletal myogenesis through coordinate regulation of muscle differentiation genes. Mol Cell Biol 2003, 23:4991–5004.
21. Cherry J, Karschner V, Jones H, Pekala PH. HuR, an RNA-binding protein, involved in the control of cellular differentiation. In Vivo 2006, 20:17–23.
22. Katsanou V, Papadaki O, Milatos S, Blackshear PJ, Anderson P, Kollias G, Kontoyiannis DL. HuR as a negative posttranscriptional modulator in inflammation. Mol Cell 2005, 19:777–789.
23. Gantt K, Cherry J, Tenney R, Karschner V, Pekala PH. An early event in adipogenesis, the nuclear selection of the CCAAT enhancer-binding protein β (C/EBPβ) mRNA by HuR and its translocation to the cytosol. J Biol Chem 2005, 280:24768–24774.
24. Srikantan S, Gorospe M. HuR function in disease. Front Biosci 2012, 17:189–205.
25. Lu YC, Chang SH, Hafner M, Li X, Tuschl T, Elemento O, Hla T. ELAVL1 modulates transcriptome-wide miRNA binding in murine macrophages. Cell Rep 2014, 9:2330–2343.
26. Poria DK, Guha A, Nandi I, Ray PS. RNA-binding protein HuR sequesters microRNA-21 to prevent translation repression of proinflammatory tumor suppressor gene programmed cell death 4. Oncogene 2015, 35:1703–1715.
27. Yoon JH, Abdelmohsen K, Kim J, Yang X, Martindale JL, Tominaga-Yamanaka K, White EJ, Orjalo AV, Rinn JL, Kreft SG, et al. Scaffold function of long non-coding RNA HOTAIR in protein ubiquitination. Nat Commun 2013, 4:2939.
28. Yoon JH, Abdelmohsen K, Srikantan S, Yang X, Martindale JL, De S, Huarte M, Zhan M, Becker KG, Gorospe M. LincRNA-p21 suppresses target mRNA translation. Mol Cell 2012, 47:648–655.
29. Kang MJ, Ryu BK, Lee MG, Han J, Lee JH, Ha TK, Byun DS, Chae KS, Lee BH, Chun HS, et al. NF-kB activates transcription of the RNA-binding factor HuR, via PI3K-AKT signaling, to promote gastric tumorigenesis. Gastroenterology 2008, 135:2030–2042.
30. Pullmann R Jr, Kim HH, Abdelmohsen K, Lal A, Martindale JL, Yang X, Gorospe M. Analysis of turnover and translation regulatory RNA-binding protein expression through binding to cognate mRNAs. Mol Cell Biol 2007, 27:6265–6278.
31. Abdelmohsen K, Kim MM, Srikantan S, Mercken EM, Brennan SE, Wilson GM, Cabo R, Gorospe M. miR-519 suppresses tumor growth by reducing HuR levels. Cell Cycle 2010, 9:1354–1359.
32. Guo X, Connick MC, Vanderhoof J, Ishak MA, Hartley RS. MicroRNA-16 modulates HuR regulation of cyclin E1 in breast cancer cells. Int J Mol Sci 2015, 16:7112–7132.
33. Guo J, Li M, Meng X, Sui J, Dou L, Tang W, Huang X, Man Y, Wang S, Li J. MiR-291b-3p induces apoptosis in liver cell line NCTC1469 by reducing the level of RNA-binding protein HuR. Cell Physiol Biochem 2014, 33:810–822.
34. Roff AN, Craig TJ, August A, Stellato C, Ishmael FT. MicroRNA-570-3p regulates HuR and cytokine expression in airway epithelial cells. Am J Clin Exp Immunol 2014, 3:68–83.
35. Guo X, Wu Y, Hartley RS. MicroRNA-125a represses cell growth by targeting HuR in breast cancer. RNA Biol 2009, 6:575–583.
36. Fan XC, Steitz JA. HNS, a nuclear-cytoplasmic shuttling sequence in HuR. Proc Natl Acad Sci USA 1998, 95:15293–15298.
37. Keene JD. Why is Hu where? Shuttling of early-response-gene messenger RNA subsets. Proc Natl Acad Sci USA 1999, 96:5–7.
38. Rebane A, Aab A, Steitz JA. Transportins 1 and 2 are redundant nuclear import factors for hnRNP A1 and HuR. RNA 2004, 10:590–599.
39. Gallouzi IE, Brennan CM, Steitz JA. Protein ligands mediate the CRM1-dependent export of HuR in response to heat shock. RNA 2001, 7:1348–1361.
40. Stock J, Da Re S. Signal transduction: response regulators on and off. Curr Biol 2000, 10:R420–R424.
41. Scheiba RM, Aroca A, Diaz-Moreno I. HuR thermal stability is dependent on domain binding and upon phosphorylation. Eur Biophys J 2012, 41:597–605.
42. Filippova N, Yang X, Nabors LB. Growth factor dependent regulation of centrosome function and genomic instability by HuR. Biomolecules 2015, 5:263–281.
43. Yoon JH, Abdelmohsen K, Srikantan S, Guo R, Yang X, Martindale JL, Gorospe M. Tyrosine phosphorylation of HuR by JAK3 triggers dissociation and degradation of HuR target mRNAs. Nucleic Acids Res 2014, 42:1196–1208.
44. Abdelmohsen K, Pullmann R Jr, Lal A, Kim HH, Galban S, Yang X, Blethrow JD, Walker M, Shubert J, Gillespie DA, et al. Phosphorylation of HuR by Chk2 regulates SIRT1 expression. Mol Cell 2007, 25:543–557.
45. Masuda K, Abdelmohsen K, Kim MM, Srikantan S, Lee EK, Tominaga K, Selimyan R, Martindale JL, Yang X, Lehrmann E, et al. Global dissociation of HuR-mRNA complexes promotes cell survival after ionizing radiation. EMBO J 2011, 30:1040–1053.
46. Yu TX, Wang PY, Rao JN, Zou T, Liu L, Xiao L, Gorospe M, Wang JY. Chk2-dependent HuR phosphorylation regulates occludin mRNA translation and epithelial barrier function. Nucleic Acids Res 2011, 39:8472–8487.
47. Akaike Y, Masuda K, Kuwano Y, Nishida K, Kajita K, Kurokawa K, Satake Y, Shoda K, Imoto I, Rokutan K. HuR regulates alternative splicing of the TRA2β gene in human colon cancer cells under oxidative stress. Mol Cell Biol 2014, 34:2857–2873.
48. Abdelmohsen K, Srikantan S, Yang X, Lal A, Kim HH, Kuwano Y, Galban S, Becker KG, Kamara D, de Cabo R, et al. Ubiquitin-mediated proteolysis of HuR by heat shock. EMBO J 2009, 28:1271–1282.
49. Liu L, Rao JN, Zou T, Xiao L, Wang PY, Turner DJ, Gorospe M, Wang JY. Polyamines regulate c-Myc translation through Chk2-dependent HuR phosphorylation. Mol Biol Cell 2009, 20:4885–4898.
50. 1/S checkpoint. Mol Cell Biol 2009, 29:4341–4351.
51. Liao WL, Wang WC, Chang WC, Tseng JT. The RNA-binding protein HuR stabilizes cytosolic phospholipase A2α mRNA under interleukin-1β treatment in non-small cell lung cancer A549 Cells. J Biol Chem 2011, 286:35499–35508.
52. Doller A, Huwiler A, Muller R, Radeke HH, Pfeilschifter J, Eberhardt W. Protein kinase C α-dependent phosphorylation of the mRNA-stabilizing factor HuR: implications for posttranscriptional regulation of cyclooxygenase-2. Mol Biol Cell 2007, 18:2137–2148.
53. Kim HS, Wilce MC, Yoga YM, Pendini NR, Gunzburg MJ, Cowieson NP, Wilson GM, Williams BR, Gorospe M, Wilce JA. Different modes of interaction by TIAR and HuR with target RNA and DNA. Nucleic Acids Res 2011, 39:1117–1130.
54. Lucchesi C, Sheikh MS, Huang Y. Negative regulation of RNA-binding protein HuR by tumor-suppressor ECRG2. Oncogene 2016, 35:2565–2573.
55. Kim HH, Abdelmohsen K, Lal A, Pullmann R Jr, Yang X, Galban S, Srikantan S, Martindale JL, Blethrow J, Shokat KM, et al. Nuclear HuR accumulation through phosphorylation by Cdk1. Genes Dev 2008, 22:1804–1815.
56. Filippova N, Yang X, King P, Nabors LB. Phosphoregulation of the RNA-binding protein Hu antigen R (HuR) by Cdk5 affects centrosome function. J Biol Chem 2012, 287:32277–32287.
57. Li H, Park S, Kilburn B, Jelinek MA, Henschen-Edman A, Aswad DW, Stallcup MR, Laird-Offringa IA. Lipopolysaccharide-induced methylation of HuR, an mRNA-stabilizing protein, by CARM1. Coactivator-associated arginine methyltransferase. J Biol Chem 2002, 277:44623–44630.
58. Mazroui R, Di Marco S, Clair E, von Roretz C, Tenenbaum SA, Keene JD, Saleh M, Gallouzi IE. Caspase-mediated cleavage of HuR in the cytoplasm contributes to pp32/PHAP-I regulation of apoptosis. J Cell Biol 2008, 180:113–127.
59. Kim HH, Yang X, Kuwano Y, Gorospe M. Modification at HuR(S242) alters HuR localization and proliferative influence. Cell Cycle 2008, 7:3371–3377.
60. Embade N, Fernandez-Ramos D, Varela-Rey M, Beraza N, Sini M, Gutierrez de Juan V, Woodhoo A, Martinez-Lopez N, Rodriguez-Iruretagoyena B, Bustamante FJ, et al. Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. Hepatology 2012, 55:1237–1248.
61. de Sousa GF, Lima Mde A, Custodio DF, Freitas VM, Monteiro G. Chemogenomic study of carboplatin in Saccharomyces cerevisiae: inhibition of the NEDDylation process overcomes cellular resistance mediated by HuR and Cullin proteins. PLoS One 2015, 10:e0145377.
62. Chu PC, Chuang HC, Kulp SK, Chen CS. The mRNA-stabilizing factor HuR protein is targeted by β-TrCP protein for degradation in response to glycolysis inhibition. J Biol Chem 2012, 287:43639–43650.
63. Zhou HL, Geng C, Luo G, Lou H. The p97-UBXD8 complex destabilizes mRNA by promoting release of ubiquitinated HuR from mRNP. Genes Dev 2013, 27:1046–1058.
64. Doller A, Winkler C, Azrilian I, Schulz S, Hartmann S, Pfeilschifter J, Eberhardt W. High-constitutive HuR phosphorylation at Ser 318 by PKCδ propagates tumor relevant functions in colon carcinoma cells. Carcinogenesis 2011, 32:676–685.
65. Latorre E, Castiglioni I, Gatto P, Carelli S, Quattrone A, Provenzani A. Loss of protein kinase Cδ/HuR interaction is necessary to doxorubicin resistance in breast cancer cell lines. J Pharmacol Exp Ther 2014, 349:99–106.
66. Satyanarayana A, Kaldis P. Mammalian cell-cycle regulation: several Cdks, numerous cyclins and diverse compensatory mechanisms. Oncogene 2009, 28:2925–2939.
67. Wang W, Caldwell MC, Lin S, Furneaux H, Gorospe M. HuR regulates cyclin A and cyclin B1 mRNA stability during cell proliferation. EMBO J 2000, 19:2340–2350.
68. Kim HH, Gorospe M. Phosphorylated HuR shuttles in cycles. Cell Cycle 2008, 7:3124–3126.
69. Tsai LH, Takahashi T, Caviness VS Jr, Harlow E. Activity and expression pattern of cyclin-dependent kinase 5 in the embryonic mouse nervous system. Development 1993, 119:1029–1040.
70. Ubersax JA, Woodbury EL, Quang PN, Paraz M, Blethrow JD, Shah K, Shokat KM, Morgan DO. Targets of the cyclin-dependent kinase Cdk1. Nature 2003, 425:859–864.
71. Al-Khalaf HH, Aboussekhra A. ATR controls the UV-related upregulation of the CDKN1A mRNA in a Cdk1/HuR-dependent manner. Mol Carcinog 2014, 53:979–987.
72. Cuenda A, Rousseau S. p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773, 2007:1358–1375.
73. Wang X, McGowan CH, Zhao M, He L, Downey JS, Fearns C, Wang Y, Huang S, Han J. Involvement of the MKK6-p38γ cascade in γ-radiation-induced cell cycle arrest. Mol Cell Biol 2000, 20:4543–4552.
74. Degese MS, Tanos T, Naipauer J, Gingerich T, Chiappe D, Echeverria P, LaMarre J, Gutkind JS, Coso OA. An interplay between the p38 MAPK pathway and AUBPs regulates c-fos mRNA stability during mitogenic stimulation. Biochem J 2015, 467:77–90.
75. Dempsey EC, Newton AC, Mochly-Rosen D, Fields AP, Reyland ME, Insel PA, Messing RO. Protein kinase C isozymes and the regulation of diverse cell responses. Am J Physiol Lung Cell Mol Physiol 2000, 279:L429–L438.
76. Mackay HJ, Twelves CJ. Targeting the protein kinase C family: are we there yet? Nat Rev Cancer 2007, 7:554–562.
77. Doller A, Schlepckow K, Schwalbe H, Pfeilschifter J, Eberhardt W. Tandem phosphorylation of serines 221 and 318 by protein kinase Cδ coordinates mRNA binding and nucleocytoplasmic shuttling of HuR. Mol Cell Biol 2010, 30:1397–1410.
78. Barker A, Epis MR, Porter CJ, Hopkins BR, Wilce MC, Wilce JA, Giles KM, Leedman PJ. Sequence requirements for RNA binding by HuR and AUF1. J Biochem 2012, 151:423–437.
79. Meisner NC, Hintersteiner M, Mueller K, Bauer R, Seifert JM, Naegeli HU, Ottl J, Oberer L, Guenat C, Moss S, et al. Identification and mechanistic characterization of low-molecular-weight inhibitors for HuR. Nat Chem Biol 2007, 3:508–515.
80. Fialcowitz-White EJ, Brewer BY, Ballin JD, Willis CD, Toth EA, Wilson GM. Specific protein domains mediate cooperative assembly of HuR oligomers on AU-rich mRNA-destabilizing sequences. J Biol Chem 2007, 282:20948–20959.
81. Steinberg SF. Distinctive activation mechanisms and functions for protein kinase Cδ. Biochem J 2004, 384:449–459.
82. Pongracz J, Clark P, Neoptolemos JP, Lord JM. Expression of protein kinase C isoenzymes in colorectal cancer tissue and their differential activation by different bile acids. Int J Cancer 1995, 61:35–39.
83. Liwak-Muir U, Dobson CC, Naing T, Wylie Q, Chehade L, Baird SD, Chakraborty PK, Holcik M. ERK8 is a novel HuR kinase that regulates tumour suppressor PDCD4 through a miR-21 dependent mechanism. Oncotarget 2016, 7:1439–1450.
84. Bergalet J, Fawal M, Lopez C, Desjobert C, Lamant L, Delsol G, Morello D, Espinos E. HuR-mediated control of C/EBPβ mRNA stability and translation in ALK-positive anaplastic large cell lymphomas. Mol Cancer Res 2011, 9:485–496.
85. Gummadi L, Taylor L, Curthoys NP. Concurrent binding and modifications of AUF1 and HuR mediate the pH-responsive stabilization of phosphoenolpyruvate carboxykinase mRNA in kidney cells. Am J Physiol Renal Physiol 2012, 303:F1545–F1554.
86. Dickson AM, Anderson JR, Barnhart MD, Sokoloski KJ, Oko L, Opyrchal M, Galanis E, Wilusz CJ, Morrison TE, Wilusz J. Dephosphorylation of HuR protein during alphavirus infection is associated with HuR relocalization to the cytoplasm. J Biol Chem 2012, 287:36229–36238.
87. Bedford MT, Clarke SG. Protein arginine methylation in mammals: who, what, and why. Mol Cell 2009, 33:1–13.
88. Fackelmayer FO. Protein arginine methyltransferases: guardians of the Arg? Trends Biochem Sci 2005, 30:666–671.
89. Schurter BT, Koh SS, Chen D, Bunick GJ, Harp JM, Hanson BL, Henschen-Edman A, Mackay DR, Stallcup MR, Aswad DW. Methylation of histone H3 by coactivator-associated arginine methyltransferase 1. Biochemistry 2001, 40:5747–5756.
90. Xu W, Chen H, Du K, Asahara H, Tini M, Emerson BM, Montminy M, Evans RM. A transcriptional switch mediated by cofactor methylation. Science 2001, 294:2507–2511.
91. Pang L, Tian H, Chang N, Yi J, Xue L, Jiang B, Gorospe M, Zhang X, Wang W. Loss of CARM1 is linked to reduced HuR function in replicative senescence. BMC Mol Biol 2013, 14:15.
92. Calvanese V, Lara E, Suarez-Alvarez B, Abu Dawud R, Vazquez-Chantada M, Martinez-Chantar ML, Embade N, Lopez-Nieva P, Horrillo A, Hmadcha A, et al. Sirtuin 1 regulation of developmental genes during differentiation of stem cells. Proc Natl Acad Sci USA 2010, 107:13736–13741.
93. Vigouroux C, Casse JM, Battaglia-Hsu SF, Brochin L, Luc A, Paris C, Lacomme S, Gueant JL, Vignaud JM, Gauchotte G. Methyl(R217)HuR and MCM6 are inversely correlated and are prognostic markers in non small cell lung carcinoma. Lung Cancer 2015, 89:189–196.
94. Hershko A, Ciechanover A. The ubiquitin system. Annu Rev Biochem 1998, 67:425–479.
95. Bonelli MA, Alfieri RR, Desenzani S, Petronini PG, Borghetti AF. Proteasome inhibition increases HuR level, restores heat-inducible HSP72 expression and thermotolerance in WI-38 senescent human fibroblasts. Exp Gerontol 2004, 39:423–432.
96. Xirodimas DP. Novel substrates and functions for the ubiquitin-like molecule NEDD8. Biochem Soc Trans 2008, 36:802–806.
97. Pan ZQ, Kentsis A, Dias DC, Yamoah K, Wu K. Nedd8 on cullin: building an expressway to protein destruction. Oncogene 2004, 23:1985–1997.
98. von Roretz C, Gallouzi IE. Protein kinase RNA/FADD/caspase-8 pathway mediates the proapoptotic activity of the RNA-binding protein human antigen R (HuR). J Biol Chem 2010, 285:16806–16813.
99. van der Giessen K, Gallouzi IE. Involvement of transportin 2-mediated HuR import in muscle cell differentiation. Mol Biol Cell 2007, 18:2619–2629.
100. Beauchamp P, Nassif C, Hillock S, van der Giessen K, von Roretz C, Jasmin BJ, Gallouzi IE. The cleavage of HuR interferes with its transportin-2-mediated nuclear import and promotes muscle fiber formation. Cell Death Differ 2010, 17:1588–1599.