Journal
NUCLEIC ACIDS RESEARCH
Volume 42, Issue 17, Pages 11011-11024Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gku814
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Funding
- Equipe Labellisee of the French Ligue Nationale contre le Cancer
- CNRS
- Programme Blanc of the Agence Nationale pour la Recherche (ANR)
- regional Languedoc-Roussillon Ligue contre le Cancer
- Ministry of Higher Education and Research (MESR)
- Association pour la Recherche contre le Cancer (ARC)
- The Ligue Nationale contre le Cancer
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Plau codes for the urokinase-type plasminogen activator (uPA), critical in cancer metastasis. While the mechanisms driving its overexpression in tumorigenic processes are unknown, it is regulated by the AP-1 transcriptional complex in diverse situations. The AP-1 component Fra-1 being overexpressed in aggressive breast cancers, we have addressed its role in the overexpression of Plau in the highly metastatic breast cancer model cell line MDA-MB231 using ChIP, pharmacological and RNAi approaches. Plau transcription appears controlled by 2 AP-1 enhancers located -1.9 (ABR-1.9) and -4.1 kb (ABR-4.1) upstream of the transcription start site (TSS) of the uPA-coding mRNA, Plau-001, that bind Fra-1. Surprisingly, RNA Pol II is not recruited only at the Plau-001 TSS but also upstream in the ABR-1.9 and ABR-4.1 region. Most Pol II molecules transcribe short and unstable RNAs while tracking down toward the TSS, where there are converted into Plau-001 mRNA-productive species. Moreover, a minority of Pol II molecules transcribes a low abundance mRNA of unknown function called Plau-004 from the ABR-1.9 domain, whose expression is tempered by Fra-1. Thus, we unveil a heretofore-unsuspected transcriptional complexity at Plau in a reference metastatic breast cancer cell line with pleiotropic effects for Fra-1, providing novel information on AP-1 transcriptional action.
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