p63 - Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis.
Idiopathic pulmonary fibrosis (IPF) is the most common lung disease predisposing lung cancer. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 (TGF beta1)-treated airway epithelial cells (BEAS-2B). The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including p63, jagged 1 (jag1) and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaNp63alpha was the dominant isoform of p63 in our experimental model. Immunohistochemical analysis demonstrated the expression of p63 and jag1 in lung tissues of IPF. Inhibition of p63 with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of p63 was totally suppressed by N-acetyl-l-cysteine (NAC), but not by dexamethasone or pirfenidone. Thus, the p63-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu.
Murata
Kengo
K
Department of Human Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Ota
Satoshi
S
Niki
Toshiro
T
Goto
Akiteru
A
Li
Chih-Ping
CP
Ruriko
Urbiztondo Maria Rhea
UM
Ishikawa
Shumpei
S
Aburatani
Hiroyuki
H
Kuriyama
Takayuki
T
Fukayama
Masashi
M
D000111:Acetylcysteine / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000072100:Jagged-1 Protein; D053547:Keratin-14 / Q000235:genetics / Q000378:metabolism; D053553:Keratin-6 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008679:Metaplasia / Q000378:metabolism / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D020545:Respiratory Mucosa / Q000166:cytology*; D000072099:Serrate-Jagged Proteins; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
D015415:Biomarkers; D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; D000072100:Jagged-1 Protein; C507540:KRT14 protein, human; D053547:Keratin-14; D053553:Keratin-6; D008565:Membrane Proteins; D020033:Protein Isoforms; D011498:Protein Precursors; D034741:RNA, Small Interfering; D000072099:Serrate-Jagged Proteins; C115051:TP63 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C032253:involucrin; D000111:Acetylcysteine