p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway.
The mitogen-activated protein kinase (MAPK) p38alpha controls inflammatory responses and cell proliferation. Using mice carrying conditional Mapk14 (also known as p38alpha) alleles, we investigated its function in postnatal development and tumorigenesis. When we specifically deleted Mapk14 in the mouse embryo, fetuses developed to term but died shortly after birth, probably owing to lung dysfunction. Fetal hematopoietic cells and embryonic fibroblasts deficient in p38alpha showed increased proliferation resulting from sustained activation of the c-Jun N-terminal kinase (JNK)-c-Jun pathway. Notably, in chemical-induced liver cancer development, mice with liver-specific deletion of Mapk14 showed enhanced hepatocyte proliferation and tumor development that correlated with upregulation of the JNK-c-Jun pathway. Furthermore, inactivation of JNK or c-Jun suppressed the increased proliferation of Mapk14-deficient hepatocytes and tumor cells. These results demonstrate a new mechanism whereby p38alpha negatively regulates cell proliferation by antagonizing the JNK-c-Jun pathway in multiple cell types and in liver cancer development.
Hui
Lijian
L
Research Institute of Molecular Pathology, A-1030 Vienna, Austria.
Bakiri
Latifa
L
Mairhorfer
Andreas
A
Schweifer
Norbert
N
Haslinger
Christian
C
Kenner
Lukas
L
Komnenovic
Vukoslav
V
Scheuch
Harald
H
Beug
Hartmut
H
Wagner
Erwin F
EF
D000818:Animals; D049109:Cell Proliferation; D004912:Erythrocytes / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction
D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14