Rac1 signalling modulates a STAT5/BCL-6 transcriptional switch on cell-cycle-associated target gene promoters.
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, p15(INK4B), 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.
Department of Genetics, National Health Institute Dr. Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisbon, Portugal.
Patrícia
P
Barros
Eric W-F
EW
Lam
Peter
P
Jordan
Paulo
P
Matos
D002453:Cell Cycle / Q000235:genetics*; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D006801:Humans; D011401:Promoter Regions, Genetic; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014158:Transcription, Genetic; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D051560:Proto-Oncogene Proteins c-bcl-6; D050799:STAT5 Transcription Factor; D020830:rac1 GTP-Binding Protein