title: MyoD and E-protein heterodimers switch rhabdomyosarcoma cells from an arrested myoblast phase to a differentiated state.
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.
authors.affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Yang
authors.forename: Kyle L
authors.initials: KL
authors.lastname: MacQuarrie
authors.forename: Erwin
authors.initials: E
authors.lastname: Analau
authors.forename: Ashlee E
authors.initials: AE
authors.lastname: Tyler
authors.forename: F Jeffery
authors.initials: FJ
authors.lastname: Dilworth
authors.forename: Yi
authors.initials: Y
authors.lastname: Cao
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Diede
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Tapscott
mesh_terms: D000595:Amino Acid Sequence; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D008969:Molecular Sequence Data; D017570:MyoD Protein / Q000502:physiology*; D032446:Myoblasts / Q000166:cytology* / Q000502:physiology; D055503:Protein Multimerization; D019154:Protein Splicing; D012208:Rhabdomyosarcoma / Q000378:metabolism* / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D017570:MyoD Protein; C057363:MyoD1 myogenic differentiation protein; C407909:TCF3 protein, human