FoxO3a and BCR-ABL regulate cyclin D2 transcription through a STAT5/BCL6-dependent mechanism.
Cell cycle arrest by FoxO transcription factors involves transcriptional repression of cyclin D, although the exact mechanism remains unclear. In this study, we used the BCR-ABL-expressing cell line BV173 as a model system to investigate the mechanisms whereby FoxO3a regulates cyclin D2 expression. Inhibition of BCR-ABL by STI571 results in down-regulation of cyclin D2 expression, activation of FoxO3a activity, and up-regulation of BCL6 expression. Using reporter gene assays, we demonstrate that STI571, FoxO3a, and BCL6 can repress cyclin D2 transcription through a STAT5/BCL6 site located within the cyclin D2 promoter. We propose that BCR-ABL inhibition leads to FoxO3a activation, which in turn induces the expression of BCL6, culminating in the repression of cyclin D2 transcription through this STAT5/BCL6 site. This process was verified by mobility shift and chromatin immunoprecipitation analyses. We find that conditional activation of FoxO3a leads to accumulation of BCL6 and down-regulation of cyclin D2 at protein and mRNA levels. Furthermore, silencing of FoxO3a and BCL6 in BCR-ABL-expressing cells abolishes STI571-mediated effects on cyclin D2. This report establishes the signaling events whereby BCR-ABL signals are relayed to cyclin D2 to mediate cell cycle progression and defines a potential mechanism by which FoxO proteins regulate cyclin D2 expression.
Fernández de Mattos
Silvia
S
Cancer Research-UK Laboratories, Department of Cancer Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Essafi
Abdelkader
A
Soeiro
Inês
I
Pietersen
Alexandra M
AM
Birkenkamp
Kim U
KU
Edwards
Corinne S
CS
Martino
Anthony
A
Nelson
Brad H
BH
Francis
Julia M
JM
Jones
Marius C
MC
Brosens
Jan J
JJ
Coffer
Paul J
PJ
Lam
Eric W-F
EW
D001483:Base Sequence; D001549:Benzamides; D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics* / Q000378:metabolism; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D008894:Milk Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051560:Proto-Oncogene Proteins c-bcl-6; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects
C084103:BCL6 protein, human; D001549:Benzamides; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D008894:Milk Proteins; D009687:Nuclear Proteins; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D051560:Proto-Oncogene Proteins c-bcl-6; D011743:Pyrimidines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl