Inactivation of AP1 proteins by a nuclear serine protease precedes the onset of radiation-induced fibrosing alveolitis.
Radiation-induced lung damage comprises inflammation (alveolitis) as well as disturbed regulation of cell differentiation and proliferation (fibrosis). The transcriptional regulation of this process is poorly understood. One key transcription factor involved in the regulation of proliferation and differentiation is AP1 (activator protein 1). The present study examined changes in the DNA-binding activity of AP1 after irradiation and defined the underlying molecular mechanisms in an animal model. The right lungs of Fischer rats received a single radiation dose of 20 Gy. Lung tissue was tested for AP1 DNA-binding activity, AP1 mRNA, and levels of AP1 proteins as well as for c-Jun specific proteolytic activity. After an initial increase, the AP1 DNA-binding activity was completely lost starting at 5.5 weeks after irradiation, which is 2.5 weeks before the onset of fibrosing alveolitis. This was not caused by reduction of mRNA levels or size. Instead, a selective nuclear cleavage of c-Jun by a serine protease caused the loss of AP1 activity. Considering the central role of AP1 in cell proliferation and differentiation and the strict timely correlation to the onset of the disease, the complete loss of AP1 function is likely to play a critical role in radiation-induced fibrosing alveolitis.
Haase
Michael G
MG
Department of Pathology, Dresden University of Technology, Germany. Michael.Haase@OncoRay.de
Klawitter
Anke
A
Bierhaus
Angelika
A
Yokoyama
Kazunari K
KK
Kasper
Michael
M
Geyer
Peter
P
Baumann
Michael
M
Baretton
Gustavo B
GB
D000818:Animals; D002467:Cell Nucleus / Q000201:enzymology* / Q000528:radiation effects*; D005260:Female; D006262:Health; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000528:radiation effects; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D012697:Serine Endopeptidases / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D012697:Serine Endopeptidases