RRC ID 52103
Author Liu Z, Yanagisawa K, Griesing S, Iwai M, Kano K, Hotta N, Kajino T, Suzuki M, Takahashi T.
Title TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas.
Journal 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.
Volume 36(26)
Pages 3740-3748
Published 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
Times Cited 10
Human and Animal Cells PC-9(RCB4455)