p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation.
Stem cell function is central for the maintenance of normal tissue homeostasis. Here we show that deletion of p38alpha mitogen-activated protein (MAP) kinase in adult mice results in increased proliferation and defective differentiation of lung stem and progenitor cells both in vivo and in vitro. We found that p38alpha positively regulates factors such as CCAAT/enhancer-binding protein that are required for lung cell differentiation. In addition, p38alpha controls self-renewal of the lung stem and progenitor cell population by inhibiting proliferation-inducing signals, most notably epidermal growth factor receptor. As a consequence, the inactivation of p38alpha leads to an immature and hyperproliferative lung epithelium that is highly sensitized to K-Ras(G12V)-induced tumorigenesis. Our results indicate that by coordinating proliferation and differentiation signals in lung stem and progenitor cells, p38alpha has a key role in the regulation of lung cell renewal and tumorigenesis.
Ventura
Juan José
JJ
CNIO (Spanish National Cancer Center), Melchor Fernández Almagro 3, 28029 Madrid, Spain. jjventura@cnio.es
Tenbaum
Stephan
S
Perdiguero
Eusebio
E
Huth
Marion
M
Guerra
Carmen
C
Barbacid
Mariano
M
Pasparakis
Manolis
M
Nebreda
Angel R
AR
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D005260:Female; D011905:Genes, ras / Q000502:physiology; D007124:Immunoenzyme Techniques; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000502:physiology*; D016755:Proto-Oncogene Proteins c-jun / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
D016755:Proto-Oncogene Proteins c-jun; D048031:JNK Mitogen-Activated Protein Kinases; D048308:Mitogen-Activated Protein Kinase 14