RRC ID |
52103
|
著者 |
Liu Z, Yanagisawa K, Griesing S, Iwai M, Kano K, Hotta N, Kajino T, Suzuki M, Takahashi T.
|
タイトル |
TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.
|
ジャーナル |
Oncogene
|
Abstract |
TTF-1, also known as NKX2-1, is a transcription factor that has indispensable roles in both lung development and physiology. We and others have reported that TTF-1 frequently exhibits high expression with increased copy number in lung adenocarcinomas, and also has a role as a lineage-survival oncogene through transcriptional activation of crucial target genes including ROR1 and LMO3. In the present study, we employed a global proteomic search for proteins that interact with TTF-1 in order to provide a more comprehensive picture of this still enigmatic lineage-survival oncogene. Our results unexpectedly revealed a function independent of its transcriptional activity, as TTF-1 was found to interact with DDB1 and block its binding to CHK1, which in turn attenuated ubiquitylation and subsequent degradation of CHK1. Furthermore, TTF-1 overexpression conferred resistance to cellular conditions under DNA replication stress (RS) and prevented an increase in consequential DNA double-strand breaks, as reflected by attenuated induction of pCHK2 and γH2AX. Our findings suggest that the novel non-transcriptional function of TTF-1 identified in this study may contribute to lung adenocarcinoma development by conferring tolerance to DNA RS, which is known to be inherently elicited by activation of various oncogenes.
|
巻・号 |
36(26)
|
ページ |
3740-3748
|
公開日 |
2017-6-29
|
DOI |
10.1038/onc.2016.524
|
PII |
onc2016524
|
PMID |
28192407
|
MeSH |
Adenocarcinoma / genetics*
Adenocarcinoma / metabolism*
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Cell Line, Tumor
Checkpoint Kinase 1 / genetics
Checkpoint Kinase 1 / metabolism
DNA Breaks, Double-Stranded
DNA Replication / physiology*
DNA, Neoplasm / biosynthesis
DNA, Neoplasm / genetics
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism*
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology
Transcription Factors
Transcription, Genetic
Ubiquitination
|
IF |
7.971
|
引用数 |
10
|
リソース情報 |
ヒト・動物細胞 |
PC-9(RCB4455) |