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Rac1 signalling modulates a STAT5/BCL-6 transcriptional switch on cell-cycle-associated target gene promoters

Title: Rac1 signalling modulates a STAT5/BCL-6 transcriptional switch on cell-cycle-associated target gene promoters
Authors: Barros, P
Lam, EW-F
Jordan, P
Matos, P
Item Type: Journal Article
Abstract: Gene expression depends on binding of transcriptional regulators to gene promoters, a process controlled by signalling pathways. The transcriptional repressor B-cell lymphoma (BCL)-6 downregulates genes involved in cell-cycle progression and becomes inactivated following phosphorylation by the Rac1 GTPase-activated protein kinase PAK1. Interestingly, the DNA motifs recognized by BCL-6 and signal transducers and activators of transcription 5 (STAT5) are similar. Because STAT5 stimulation in epithelial cells can also be triggered by Rac1 signalling, we asked whether both factors have opposing roles in transcriptional regulation and whether Rac1 signalling may coordinate a transcription factor switch. We used chromatin immunoprecipitation to show that active Rac1 promotes release of the repressor BCL-6 while increasing binding of STAT5A to a BCL-6-regulated reporter gene. We further show in colorectal cell lines that the endogenous activation status of the Rac1/PAK1 pathway correlated with the phosphorylation status of BCL-6 and STAT5A. Three cellular genes (cyclin D2, p15INK4B, small ubiquitin-like modifier 1) were identified to be inversely regulated by BCL-6 and STAT5A and responded to Rac1 signalling with increased expression and corresponding changes in promoter occupancy. Together, our data show that Rac1 signalling controls a group of target genes that are repressed by BCL-6 and activated by STAT5A, providing novel insights into the modulation of gene transcription by GTPase signalling.
Issue Date: 20-Jun-2012
Date of Acceptance: 22-May-2012
URI: http://hdl.handle.net/10044/1/39198
DOI: http://dx.doi.org/10.1093/nar/gks571
ISSN: 1362-4962
Publisher: Oxford University Press
Start Page: 7776
End Page: 7787
Journal / Book Title: Nucleic Acids Research
Volume: 40
Issue: 16
Copyright Statement: © The Author(s) 2012. Published by Oxford University Press. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
BIOCHEMISTRY & MOLECULAR BIOLOGY
COLORECTAL-CANCER CELLS
PROTOONCOGENE BCL-6
RHO-GTPASES
ACTIVATING PROTEIN
BREAST-CANCER
SPLICED RAC1B
STAT PROTEINS
EXPRESSION
DIFFERENTIATION
REPRESSION
Cell Cycle
Cell Line, Tumor
Gene Expression Regulation
Humans
Promoter Regions, Genetic
Proto-Oncogene Proteins c-bcl-6
STAT5 Transcription Factor
Signal Transduction
Transcription, Genetic
rac1 GTP-Binding Protein
Developmental Biology
05 Environmental Sciences
06 Biological Sciences
08 Information And Computing Sciences
Publication Status: Published
Appears in Collections:Department of Surgery and Cancer