TRIP-Br links E2F to novel functions in the regulation of cyclin E expression during cell cycle progression and in the maintenance of genomic stability.
The TRIP-Br family of transcriptional regulators (TRIP-Br1 and TRIP-Br2) has been proposed to function at E2F-responsive promoters to integrate regulatory signals provided by PHD zinc finger- and/or bromodomain-containing transcription factors. To characterize the TRIP-Br "integrator" function(s), we have employed decoy peptides (*Br1 and *Br2) to antagonize the interaction between TRIP-Br1 or TRIP-Br2 and the PHD zinc finger and/or bromodomain of other transcription factors. Antagonism of the TRIP-Br integrator function elicits anti-proliferative effects through the transcriptional downregulation of a subset of E2F-responsive genes in vivo, and induces aberrant cyclin E accumulation, leading to Geminin deregulation and caspase-3-independent cellular sub-diploidization. The observed cyclin E deregulation is attributed to the downregulation of Fbxw7, which encodes the Fbw7 receptor subunit of the SCF(FBW7) ubiquitin ligase (E3) responsible for targeting cyclin E for proteolysis. Fbxw7 is identified herein as an E2F-responsive and TRIP-Br coregulated gene. Our results demonstrate a physiologic role for TRIP-Br in coupling E2F to novel functions in the regulation of cyclin E expression during cell cycle progression to ensure the proper execution of DNA replication and the maintenance of genomic stability.
Sim
Khe Guan
KG
Department of Medicine, Faculty of Medicine, Institute of Molecular and Cell Biology, National University of Singapore, Singapore.
Zang
Zhijiang
Z
Yang
Christopher Maolin
CM
Bonventre
Joseph V
JV
Hsu
Stephen I-Hong
SI
D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019927:Cyclin E / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000235:genetics; D050684:E2F Transcription Factors / Q000378:metabolism*; D044783:F-Box Proteins / Q000235:genetics; D000073979:F-Box-WD Repeat-Containing Protein 7; D005434:Flow Cytometry; D016193:G1 Phase; D005786:Gene Expression Regulation; D042822:Genomic Instability / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000092468:Bromodomain Containing Proteins
D053148:Caspase 3; D020169:Caspases; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050684:E2F Transcription Factors; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; D009687:Nuclear Proteins; D010455:Peptides; D012333:RNA, Messenger; D015534:Trans-Activators; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; C513273:FBXW7 protein, human; C402464:SERTAD1 protein, human; C426827:SERTAD2 protein, human; D000092468:Bromodomain Containing Proteins; C505407:CASP3 protein, human