TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung adenocarcinomas
| Autor: | M. Iwai, Naoe Hotta, Zhuoran Liu, Motoshi Suzuki, Kiyoshi Yanagisawa, Keiko Kano, Sebastian Griesing, Taisuke Kajino, Takashi Takahashi |
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| Rok vydání: | 2017 |
| Předmět: |
DNA Replication
0301 basic medicine Cancer Research Lung Neoplasms Transcription Genetic Adenocarcinoma of Lung Adenocarcinoma Biology 03 medical and health sciences chemistry.chemical_compound DDB1 Growth factor receptor Cell Line Tumor Genetics Humans DNA Breaks Double-Stranded Molecular Biology Gene Transcription factor Oncogene Ubiquitination DNA replication DNA Neoplasm respiratory system Cell cycle Molecular biology Cell biology DNA-Binding Proteins 030104 developmental biology chemistry Checkpoint Kinase 1 DNA Transcription Factors |
| Zdroj: | Oncogene. 36:3740-3748 |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/onc.2016.524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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