title: Transcriptional complexity and roles of Fra-1/AP-1 at the uPA/Plau locus in aggressive breast cancer.
abstract: 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.
authors.affiliation: Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier cedex 2, France.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Moquet-Torcy
authors.affiliation: Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier cedex 2, France.
authors.forename: Claire
authors.initials: C
authors.lastname: Tolza
authors.affiliation: Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier cedex 2, France marc.piechaczyk@igmm.cnrs.fr.
authors.forename: Marc
authors.initials: M
authors.lastname: Piechaczyk
authors.affiliation: Institut de Génétique Moléculaire de Montpellier UMR 5535, CNRS, 1919 route de Mende, 34293 Montpellier cedex 5, France Université Montpellier 2, Place Eugène Bataillon, 34095 Montpellier cedex 5, France Université Montpellier 1, 5 Bd Henry IV, 34967 Montpellier cedex 2, France marc.piechaczyk@igmm.cnrs.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jariel-Encontre
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000737:chemistry; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056426:Genetic Loci; D006801:Humans; D009362:Neoplasm Metastasis; D011401:Promoter Regions, Genetic; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism / Q000502:physiology*; D018808:Transcription Factor AP-1 / Q000502:physiology*; D014158:Transcription, Genetic; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics* / Q000378:metabolism; D000099169:Fos-Related Antigen 1
chemical_list: D002843:Chromatin; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014568:Urokinase-Type Plasminogen Activator; D000099169:Fos-Related Antigen 1