MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state

Zhihong Yang, Kyle L. MacQuarrie, Erwin Analau, Ashlee E. Tyler, F. Jeffery Dilworth, Yi Cao, Scott J. Diede, Stephen J. Tapseott

Research output: Contribution to journalArticlepeer-review

65 Scopus citations

Abstract

Rhabdomyosarcomas are characterized by expression of myogenic specification genes, such as MyoD and/or My/5, 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.

Original languageEnglish (US)
Pages (from-to)694-707
Number of pages14
JournalGenes and Development
Volume23
Issue number6
DOIs
StatePublished - Mar 15 2009
Externally publishedYes

Keywords

  • E2A
  • Musculiri
  • MyoD
  • Myogenesis
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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