Induction of terminal differentiation by constitutive activation of p38 MAP kinase in human rhabdomyosarcoma cells

MyoD inhibits cell proliferation and promotes muscle differentiation. A paradoxical feature of rhabdomyosarcoma (RMS), a tumor arising from muscle precursors, is the block of the differentiation program and the deregulated proliferation despite MyoD expression. A deficiency in RMS of a factor requir...

Full description

Saved in:
Bibliographic Details
Published in:Genes & development 2000-03, Vol.14 (5), p.574-584
Main Authors: Puri, P L, Wu, Z, Zhang, P, Wood, L D, Bhakta, K S, Han, J, Feramisco, J R, Karin, M, Wang, J Y
Format: Article
Language:English
Subjects:
Animals
Calcium-Calmodulin-Dependent Protein Kinases - metabolism
Cell Differentiation
Cell Division
Cell Line
Enzyme Activation
Enzyme Induction
Humans
JNK Mitogen-Activated Protein Kinases
JNK protein
MAP Kinase Kinase 6
MAPK kinase 6
MEF2 protein
Mice
Mitogen-Activated Protein Kinases - metabolism
Muscles - cytology
MyoD protein
MyoD Protein - metabolism
p38 Mitogen-Activated Protein Kinases
Recombinant Proteins - metabolism
Research Paper
rhabdomyosarcoma
Rhabdomyosarcoma - enzymology
Rhabdomyosarcoma - pathology
Transfection
Tumor Cells, Cultured
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:MyoD inhibits cell proliferation and promotes muscle differentiation. A paradoxical feature of rhabdomyosarcoma (RMS), a tumor arising from muscle precursors, is the block of the differentiation program and the deregulated proliferation despite MyoD expression. A deficiency in RMS of a factor required for MyoD activity has been implicated by previous studies. We report here that p38 MAP kinase (MAPK) activation, which is essential for muscle differentiation, is deficient in RMS cells. Enforced induction of p38 MAPK by an activated MAPK kinase 6 (MKK6EE) restored MyoD function and enhanced MEF2 activity in RMS deficient for p38 MAPK activation, leading to growth arrest and terminal differentiation. Stress and cytokines could activate the p38 MAPK in RMS cells, however, these stimuli did not promote differentiation, possibly because they activated p38 MAPK only transiently and they also activated JNK, which could antagonize differentiation. Thus, the selective and sustained p38 MAPK activation, which is distinct from the stress-activated response, is required for differentiation and can be disrupted in human tumors.
ISSN:0890-9369
1549-5477
DOI:10.1101/gad.14.5.574