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

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...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2009-03, Vol.23 (6), p.694-707
Main Authors: Yang, Zhihong, MacQuarrie, Kyle L, Analau, Erwin, Tyler, Ashlee E, Dilworth, F Jeffery, Cao, Yi, Diede, Scott J, Tapscott, Stephen J
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Basic Helix-Loop-Helix Transcription Factors - physiology
Cell Differentiation - physiology
Cell Line
Cell Line, Tumor
Humans
Molecular Sequence Data
Myoblasts - cytology
Myoblasts - physiology
MyoD Protein - physiology
Protein Multimerization
Protein Splicing
Research Paper
Rhabdomyosarcoma - metabolism
Rhabdomyosarcoma - pathology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.1765109