Skip to main content
PMC home page
Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Sep;17(9):5550–5558. doi: 10.1128/mcb.17.9.5550

A role for the ETS domain transcription factor PEA3 in myogenic differentiation.

J M Taylor 1, E E Dupont-Versteegden 1, J D Davies 1, J A Hassell 1, J D Houlé 1, C M Gurley 1, C A Peterson 1
PMCID: PMC232403  PMID: 9271430

Abstract

Activation of adult myoblasts called satellite cells during muscle degeneration is an important aspect of muscle regeneration. Satellite cells are believed to be the only myogenic stem cells in adult skeletal muscle and the source of regenerating muscle fibers. Upon activation, satellite cells proliferate, migrate to the site of degeneration, and become competent to fuse and differentiate. We show here that the transcription factor polyomavirus enhancer activator 3 (PEA3) is expressed in adult myoblasts in vitro when they are proliferative and during the early stages of differentiation. Overexpression of PEA3 accelerates differentiation, whereas blocking of PEA3 function delays myoblast fusion. PEA3 activates gene expression following binding to the ets motif most efficiently in conjunction with the transcription factor myocyte enhancer factor 2 (MEF2). In vivo, PEA3 is expressed in satellite cells only after muscle degeneration. Taken together, these results suggest that PEA3 is an important regulator of activated satellite cell function.

Full Text

The Full Text of this article is available as a PDF (1.6 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bassuk A. G., Leiden J. M. A direct physical association between ETS and AP-1 transcription factors in normal human T cells. Immunity. 1995 Aug;3(2):223–237. doi: 10.1016/1074-7613(95)90092-6. [DOI] [PubMed] [Google Scholar]
  2. Blobel C. P., Wolfsberg T. G., Turck C. W., Myles D. G., Primakoff P., White J. M. A potential fusion peptide and an integrin ligand domain in a protein active in sperm-egg fusion. Nature. 1992 Mar 19;356(6366):248–252. doi: 10.1038/356248a0. [DOI] [PubMed] [Google Scholar]
  3. Breitbart R. E., Liang C. S., Smoot L. B., Laheru D. A., Mahdavi V., Nadal-Ginard B. A fourth human MEF2 transcription factor, hMEF2D, is an early marker of the myogenic lineage. Development. 1993 Aug;118(4):1095–1106. doi: 10.1242/dev.118.4.1095. [DOI] [PubMed] [Google Scholar]
  4. Brown T. A., McKnight S. L. Specificities of protein-protein and protein-DNA interaction of GABP alpha and two newly defined ets-related proteins. Genes Dev. 1992 Dec;6(12B):2502–2512. doi: 10.1101/gad.6.12b.2502. [DOI] [PubMed] [Google Scholar]
  5. Campion D. R. The muscle satellite cell: a review. Int Rev Cytol. 1984;87:225–251. doi: 10.1016/s0074-7696(08)62444-4. [DOI] [PubMed] [Google Scholar]
  6. Crepieux P., Coll J., Stehelin D. The Ets family of proteins: weak modulators of gene expression in quest for transcriptional partners. Crit Rev Oncog. 1994;5(6):615–638. [PubMed] [Google Scholar]
  7. Dalton S., Treisman R. Characterization of SAP-1, a protein recruited by serum response factor to the c-fos serum response element. Cell. 1992 Feb 7;68(3):597–612. doi: 10.1016/0092-8674(92)90194-h. [DOI] [PubMed] [Google Scholar]
  8. Dias P., Parham D. M., Shapiro D. N., Tapscott S. J., Houghton P. J. Monoclonal antibodies to the myogenic regulatory protein MyoD1: epitope mapping and diagnostic utility. Cancer Res. 1992 Dec 1;52(23):6431–6439. [PubMed] [Google Scholar]
  9. Edwards D. R., Rocheleau H., Sharma R. R., Wills A. J., Cowie A., Hassell J. A., Heath J. K. Involvement of AP1 and PEA3 binding sites in the regulation of murine tissue inhibitor of metalloproteinases-1 (TIMP-1) transcription. Biochim Biophys Acta. 1992 Nov 15;1171(1):41–55. doi: 10.1016/0167-4781(92)90138-p. [DOI] [PubMed] [Google Scholar]
  10. Feo S., Antona V., Barbieri G., Passantino R., Calì L., Giallongo A. Transcription of the human beta enolase gene (ENO-3) is regulated by an intronic muscle-specific enhancer that binds myocyte-specific enhancer factor 2 proteins and ubiquitous G-rich-box binding factors. Mol Cell Biol. 1995 Nov;15(11):5991–6002. doi: 10.1128/mcb.15.11.5991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Füchtbauer E. M., Westphal H. MyoD and myogenin are coexpressed in regenerating skeletal muscle of the mouse. Dev Dyn. 1992 Jan;193(1):34–39. doi: 10.1002/aja.1001930106. [DOI] [PubMed] [Google Scholar]
  12. Gille H., Sharrocks A. D., Shaw P. E. Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature. 1992 Jul 30;358(6385):414–417. doi: 10.1038/358414a0. [DOI] [PubMed] [Google Scholar]
  13. Grounds M. D., Garrett K. L., Lai M. C., Wright W. E., Beilharz M. W. Identification of skeletal muscle precursor cells in vivo by use of MyoD1 and myogenin probes. Cell Tissue Res. 1992 Jan;267(1):99–104. doi: 10.1007/BF00318695. [DOI] [PubMed] [Google Scholar]
  14. Gutman A., Wasylyk B. The collagenase gene promoter contains a TPA and oncogene-responsive unit encompassing the PEA3 and AP-1 binding sites. EMBO J. 1990 Jul;9(7):2241–2246. doi: 10.1002/j.1460-2075.1990.tb07394.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Han T. H., Prywes R. Regulatory role of MEF2D in serum induction of the c-jun promoter. Mol Cell Biol. 1995 Jun;15(6):2907–2915. doi: 10.1128/mcb.15.6.2907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hill C. S., Treisman R. Transcriptional regulation by extracellular signals: mechanisms and specificity. Cell. 1995 Jan 27;80(2):199–211. doi: 10.1016/0092-8674(95)90403-4. [DOI] [PubMed] [Google Scholar]
  17. Hipskind R. A., Büscher D., Nordheim A., Baccarini M. Ras/MAP kinase-dependent and -independent signaling pathways target distinct ternary complex factors. Genes Dev. 1994 Aug 1;8(15):1803–1816. doi: 10.1101/gad.8.15.1803. [DOI] [PubMed] [Google Scholar]
  18. Hipskind R. A., Rao V. N., Mueller C. G., Reddy E. S., Nordheim A. Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Nature. 1991 Dec 19;354(6354):531–534. doi: 10.1038/354531a0. [DOI] [PubMed] [Google Scholar]
  19. Hughes S. M., Blau H. M. Migration of myoblasts across basal lamina during skeletal muscle development. Nature. 1990 May 24;345(6273):350–353. doi: 10.1038/345350a0. [DOI] [PubMed] [Google Scholar]
  20. Janknecht R., Nordheim A. Gene regulation by Ets proteins. Biochim Biophys Acta. 1993 Dec 23;1155(3):346–356. doi: 10.1016/0304-419x(93)90014-4. [DOI] [PubMed] [Google Scholar]
  21. Karim F. D., Urness L. D., Thummel C. S., Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A., Gunther C. V., Nye J. A. The ETS-domain: a new DNA-binding motif that recognizes a purine-rich core DNA sequence. Genes Dev. 1990 Sep;4(9):1451–1453. doi: 10.1101/gad.4.9.1451. [DOI] [PubMed] [Google Scholar]
  22. Kaushal S., Schneider J. W., Nadal-Ginard B., Mahdavi V. Activation of the myogenic lineage by MEF2A, a factor that induces and cooperates with MyoD. Science. 1994 Nov 18;266(5188):1236–1240. doi: 10.1126/science.7973707. [DOI] [PubMed] [Google Scholar]
  23. Koishi K., Zhang M., McLennan I. S., Harris A. J. MyoD protein accumulates in satellite cells and is neurally regulated in regenerating myotubes and skeletal muscle fibers. Dev Dyn. 1995 Mar;202(3):244–254. doi: 10.1002/aja.1002020304. [DOI] [PubMed] [Google Scholar]
  24. Lengyel E., Klostergaard J., Boyd D. Stimulation of urokinase expression by TNF-alpha requires the activation of binding sites for the AP-1 and PEA3 transcription factors. Biochim Biophys Acta. 1995 Jul 20;1268(1):65–72. doi: 10.1016/0167-4889(95)00050-3. [DOI] [PubMed] [Google Scholar]
  25. Lengyel E., Stepp E., Gum R., Boyd D. Involvement of a mitogen-activated protein kinase signaling pathway in the regulation of urokinase promoter activity by c-Ha-ras. J Biol Chem. 1995 Sep 29;270(39):23007–23012. doi: 10.1074/jbc.270.39.23007. [DOI] [PubMed] [Google Scholar]
  26. Martin J. F., Miano J. M., Hustad C. M., Copeland N. G., Jenkins N. A., Olson E. N. A Mef2 gene that generates a muscle-specific isoform via alternative mRNA splicing. Mol Cell Biol. 1994 Mar;14(3):1647–1656. doi: 10.1128/mcb.14.3.1647. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Martin J. F., Schwarz J. J., Olson E. N. Myocyte enhancer factor (MEF) 2C: a tissue-restricted member of the MEF-2 family of transcription factors. Proc Natl Acad Sci U S A. 1993 Jun 1;90(11):5282–5286. doi: 10.1073/pnas.90.11.5282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Martin M. E., Yang X. Y., Folk W. R. Expression of a 91-kilodalton PEA3-binding protein is down-regulated during differentiation of F9 embryonal carcinoma cells. Mol Cell Biol. 1992 May;12(5):2213–2221. doi: 10.1128/mcb.12.5.2213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. McDermott J. C., Cardoso M. C., Yu Y. T., Andres V., Leifer D., Krainc D., Lipton S. A., Nadal-Ginard B. hMEF2C gene encodes skeletal muscle- and brain-specific transcription factors. Mol Cell Biol. 1993 Apr;13(4):2564–2577. doi: 10.1128/mcb.13.4.2564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Molkentin J. D., Black B. L., Martin J. F., Olson E. N. Cooperative activation of muscle gene expression by MEF2 and myogenic bHLH proteins. Cell. 1995 Dec 29;83(7):1125–1136. doi: 10.1016/0092-8674(95)90139-6. [DOI] [PubMed] [Google Scholar]
  31. Molkentin J. D., Firulli A. B., Black B. L., Martin J. F., Hustad C. M., Copeland N., Jenkins N., Lyons G., Olson E. N. MEF2B is a potent transactivator expressed in early myogenic lineages. Mol Cell Biol. 1996 Jul;16(7):3814–3824. doi: 10.1128/mcb.16.7.3814. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Monté D., Baert J. L., Defossez P. A., de Launoit Y., Stéhelin D. Molecular cloning and characterization of human ERM, a new member of the Ets family closely related to mouse PEA3 and ER81 transcription factors. Oncogene. 1994 May;9(5):1397–1406. [PubMed] [Google Scholar]
  33. Monté D., Coutte L., Baert J. L., Angeli I., Stéhelin D., de Launoit Y. Molecular characterization of the ets-related human transcription factor ER81. Oncogene. 1995 Aug 17;11(4):771–779. [PubMed] [Google Scholar]
  34. Naidu P. S., Ludolph D. C., To R. Q., Hinterberger T. J., Konieczny S. F. Myogenin and MEF2 function synergistically to activate the MRF4 promoter during myogenesis. Mol Cell Biol. 1995 May;15(5):2707–2718. doi: 10.1128/mcb.15.5.2707. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nakae K., Nakajima K., Inazawa J., Kitaoka T., Hirano T. ERM, a PEA3 subfamily of Ets transcription factors, can cooperate with c-Jun. J Biol Chem. 1995 Oct 6;270(40):23795–23800. doi: 10.1074/jbc.270.40.23795. [DOI] [PubMed] [Google Scholar]
  36. Nye J. A., Petersen J. M., Gunther C. V., Jonsen M. D., Graves B. J. Interaction of murine ets-1 with GGA-binding sites establishes the ETS domain as a new DNA-binding motif. Genes Dev. 1992 Jun;6(6):975–990. doi: 10.1101/gad.6.6.975. [DOI] [PubMed] [Google Scholar]
  37. O'Hagan R. C., Tozer R. G., Symons M., McCormick F., Hassell J. A. The activity of the Ets transcription factor PEA3 is regulated by two distinct MAPK cascades. Oncogene. 1996 Sep 19;13(6):1323–1333. [PubMed] [Google Scholar]
  38. Olson E. N., Perry M., Schulz R. A. Regulation of muscle differentiation by the MEF2 family of MADS box transcription factors. Dev Biol. 1995 Nov;172(1):2–14. doi: 10.1006/dbio.1995.0002. [DOI] [PubMed] [Google Scholar]
  39. Peterson C. A., Cho M., Rastinejad F., Blau H. M. Beta-enolase is a marker of human myoblast heterogeneity prior to differentiation. Dev Biol. 1992 Jun;151(2):626–629. doi: 10.1016/0012-1606(92)90201-q. [DOI] [PubMed] [Google Scholar]
  40. Peterson C. A., Gordon H., Hall Z. W., Paterson B. M., Blau H. M. Negative control of the helix-loop-helix family of myogenic regulators in the NFB mutant. Cell. 1990 Aug 10;62(3):493–502. doi: 10.1016/0092-8674(90)90014-6. [DOI] [PubMed] [Google Scholar]
  41. Pollock R., Treisman R. Human SRF-related proteins: DNA-binding properties and potential regulatory targets. Genes Dev. 1991 Dec;5(12A):2327–2341. doi: 10.1101/gad.5.12a.2327. [DOI] [PubMed] [Google Scholar]
  42. Primakoff P., Hyatt H., Tredick-Kline J. Identification and purification of a sperm surface protein with a potential role in sperm-egg membrane fusion. J Cell Biol. 1987 Jan;104(1):141–149. doi: 10.1083/jcb.104.1.141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Rørth P., Nerlov C., Blasi F., Johnsen M. Transcription factor PEA3 participates in the induction of urokinase plasminogen activator transcription in murine keratinocytes stimulated with epidermal growth factor or phorbol-ester. Nucleic Acids Res. 1990 Sep 11;18(17):5009–5017. doi: 10.1093/nar/18.17.5009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Sarbassov D. D., Stefanova R., Grigoriev V. G., Peterson C. A. Role of insulin-like growth factors and myogenin in the altered program of proliferation and differentiation in the NFB4 mutant muscle cell line. Proc Natl Acad Sci U S A. 1995 Nov 21;92(24):10874–10878. doi: 10.1073/pnas.92.24.10874. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Seth A., Ascione R., Fisher R. J., Mavrothalassitis G. J., Bhat N. K., Papas T. S. The ets gene family. Cell Growth Differ. 1992 May;3(5):327–334. [PubMed] [Google Scholar]
  46. Sieweke M. H., Tekotte H., Frampton J., Graf T. MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell. 1996 Apr 5;85(1):49–60. doi: 10.1016/s0092-8674(00)81081-8. [DOI] [PubMed] [Google Scholar]
  47. Taylor J. M., Davies J. D., Peterson C. A. Regulation of the myoblast-specific expression of the human beta-enolase gene. J Biol Chem. 1995 Feb 10;270(6):2535–2540. doi: 10.1074/jbc.270.6.2535. [DOI] [PubMed] [Google Scholar]
  48. Treisman R. Ternary complex factors: growth factor regulated transcriptional activators. Curr Opin Genet Dev. 1994 Feb;4(1):96–101. doi: 10.1016/0959-437x(94)90097-3. [DOI] [PubMed] [Google Scholar]
  49. Vinson C. R., LaMarco K. L., Johnson P. F., Landschulz W. H., McKnight S. L. In situ detection of sequence-specific DNA binding activity specified by a recombinant bacteriophage. Genes Dev. 1988 Jul;2(7):801–806. doi: 10.1101/gad.2.7.801. [DOI] [PubMed] [Google Scholar]
  50. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  51. Wasylyk C., Flores P., Gutman A., Wasylyk B. PEA3 is a nuclear target for transcription activation by non-nuclear oncogenes. EMBO J. 1989 Nov;8(11):3371–3378. doi: 10.1002/j.1460-2075.1989.tb08500.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Wasylyk C., Gutman A., Nicholson R., Wasylyk B. The c-Ets oncoprotein activates the stromelysin promoter through the same elements as several non-nuclear oncoproteins. EMBO J. 1991 May;10(5):1127–1134. doi: 10.1002/j.1460-2075.1991.tb08053.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Xin J. H., Cowie A., Lachance P., Hassell J. A. Molecular cloning and characterization of PEA3, a new member of the Ets oncogene family that is differentially expressed in mouse embryonic cells. Genes Dev. 1992 Mar;6(3):481–496. doi: 10.1101/gad.6.3.481. [DOI] [PubMed] [Google Scholar]
  54. Yagami-Hiromasa T., Sato T., Kurisaki T., Kamijo K., Nabeshima Y., Fujisawa-Sehara A. A metalloprotease-disintegrin participating in myoblast fusion. Nature. 1995 Oct 19;377(6550):652–656. doi: 10.1038/377652a0. [DOI] [PubMed] [Google Scholar]
  55. Yang B. S., Hauser C. A., Henkel G., Colman M. S., Van Beveren C., Stacey K. J., Hume D. A., Maki R. A., Ostrowski M. C. Ras-mediated phosphorylation of a conserved threonine residue enhances the transactivation activities of c-Ets1 and c-Ets2. Mol Cell Biol. 1996 Feb;16(2):538–547. doi: 10.1128/mcb.16.2.538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Yoganathan T., Cowie A., Hassell J. A., Sells B. H. Enhanced cell-free transcription of the ribosomal protein L32 gene by the polyoma virus enhancer PEA3 DNA-binding protein. Eur J Biochem. 1992 Jul 1;207(1):195–200. doi: 10.1111/j.1432-1033.1992.tb17037.x. [DOI] [PubMed] [Google Scholar]
  57. Yu Y. T., Breitbart R. E., Smoot L. B., Lee Y., Mahdavi V., Nadal-Ginard B. Human myocyte-specific enhancer factor 2 comprises a group of tissue-restricted MADS box transcription factors. Genes Dev. 1992 Sep;6(9):1783–1798. doi: 10.1101/gad.6.9.1783. [DOI] [PubMed] [Google Scholar]

Articles from Molecular and Cellular Biology are provided here courtesy of Taylor & Francis

RESOURCES