MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state
- Zhihong Yang1,
- Kyle L. MacQuarrie1,2,
- Erwin Analau1,
- Ashlee E. Tyler1,
- F. Jeffery Dilworth3,
- Yi Cao1,
- Scott J. Diede1 and
- Stephen J. Tapscott1,4,5
- 1Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- 2Medical Scientist Training Program, University of Washington, Seattle, Washington 98105; USA;
- 3Sprott Center for Stem Cell Research, Ottawa Health Research Institute, Ottawa, Ontario K1Y 4E9, Canada;
- 4Department of Neurology, University of Washington, Seattle, Washington 98105, USA
Abstract
Rhabdomyosarcomas are characterized by expression of myogenic specification genes, such as MyoD and/or Myf5, and some muscle structural genes in a population of cells that continues to replicate. Because MyoD is sufficient to induce terminal differentiation in a variety of cell types, we have sought to determine the molecular mechanisms that prevent MyoD activity in human embryonal rhabdomyosarcoma cells. In this study, we show that a combination of inhibitory Musculin:E-protein complexes and a novel splice form of E2A compete with MyoD for the generation of active full-length E-protein:MyoD heterodimers. A forced heterodimer between MyoD and the full-length E12 robustly restores differentiation in rhabdomyosarcoma cells and broadly suppresses multiple inhibitory pathways. Our studies indicate that rhabdomyosarcomas represent an arrested progress through a normal transitional state that is regulated by the relative abundance of heterodimers between MyoD and the full-length E2A proteins. The demonstration that multiple inhibitory mechanisms can be suppressed and myogenic differentiation can be induced in the RD rhabdomyosarcomas by increasing the abundance of MyoD:E-protein heterodimers suggests a central integrating function that can be targeted to force differentiation in muscle cancer cells.
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Footnotes
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↵5 Corresponding author.
↵E-MAIL stapscot{at}fhcrc.org; FAX (206) 667-6524.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1765109.
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Supplemental material is available at http://www.genesdev.org.
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- Received November 20, 2008.
- Accepted February 9, 2009.
- Copyright © 2009 by Cold Spring Harbor Laboratory Press