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

Publication Type:

Journal Article


Genes & development, Volume 23, Issue 6, p.694-707 (2009)


2009, Amino Acid Sequence, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cell Line, Cell Line, Tumor, Center-Authored Paper, Comparative Medicine Core Facility, Human Biology Division, Humans, Molecular Sequence Data, MYOBLASTS, MyoD Protein, Protein Multimerization, Protein Splicing, Proteomics Core Facility, Rhabdomyosarcoma, Shared Resources


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.