Oct-2 forms a complex with Oct-1 on the iNOS promoter and represses transcription by interfering with recruitment of RNA PolII by Oct-1.
Oct-1 (POU2f1) and Oct-2 (POU2f2) are members of the POU family of transcription factors. They recognize the same DNA sequence but fulfil distinct functions: Oct-1 is ubiquitous and regulates a variety of genes while Oct-2 is restricted to B-cells and neurones. Here we examine the interplay and regulatory mechanisms of these factors to control the inducible nitric oxide synthase (iNOS, NOS2). Using two breast cancer cell lines as a comparative model, we found that MCF-7 express iNOS upon cytokine stimulation while MDA-MB-231 do not. Oct-1 is present in both cell lines but MDA-MB-231 also express high levels of Oct-2. Manipulation of Oct-2 expression in these cell lines demonstrates that it is directly responsible for the repression of iNOS in MDA-MB-231. In MCF-7 cells Oct-1 binds the iNOS promoter, recruits RNA PolII and triggers initiation of transcription. In MDA-MB-231 cells, both Oct-1 and Oct-2 bind the iNOS promoter, forming a higher-order complex which fails to recruit RNA PolII, and as a consequence iNOS transcription does not proceed. Unravelling the mechanisms of transcription factor activity is paramount to the understanding of gene expression patterns that determine cell behaviour.
EPHE Laboratory, Faculty of Medicine, University of Bourgogne, 7 Boulevard Jeanne D'Arc, 21033 Dijon, France.
Fatima
F
Bentrari
EPHE Laboratory, Faculty of Medicine, University of Bourgogne, 7 Boulevard Jeanne D'Arc, 21033 Dijon, France.
Aurelie
A
Chantôme
The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Andrew
A
Knights
EPHE Laboratory, Faculty of Medicine, University of Bourgogne, 7 Boulevard Jeanne D'Arc, 21033 Dijon, France.
Jean-François
JF
Jeannin
EPHE Laboratory, Faculty of Medicine, University of Bourgogne, 7 Boulevard Jeanne D'Arc, 21033 Dijon, France The Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridge CB10 1SA, UK ap9@sanger.ac.uk.
Alena
A
Pance
D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D050811:Octamer Transcription Factor-1 / Q000378:metabolism*; D050813:Octamer Transcription Factor-2 / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012320:RNA Polymerase III / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
D050811:Octamer Transcription Factor-1; D050813:Octamer Transcription Factor-2; D012097:Repressor Proteins; D052247:Nitric Oxide Synthase Type II; D012320:RNA Polymerase III