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 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.
Puri
P L
PL
Department of Biology, University of California at San Diego, La Jolla, California 92093, USA.
Wu
Z
Z
Zhang
P
P
Wood
L D
LD
Bhakta
K S
KS
Han
J
J
Feramisco
J R
JR
Karin
M
M
Wang
J Y
JY
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D004789:Enzyme Activation; D004790:Enzyme Induction; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009132:Muscles / Q000166:cytology*; D017570:MyoD Protein / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000201:enzymology / Q000473:pathology*; D014162:Transfection; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases
D017570:MyoD Protein; D011994:Recombinant Proteins; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048669:MAP Kinase Kinase 6; C482566:MAP2K6 protein, human; C482567:Map2k6 protein, mouse