The carboxyl-terminal fragment of pro-HB-EGF reverses Bcl6-mediated gene repression.
Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a member of the EGF family, is synthesized as a type I transmembrane precursor (pro-HB-EGF). Ectodomain shedding of pro-HB-EGF yields an amino-terminal soluble ligand of EGF receptor (HB-EGF) and a carboxyl-terminal fragment (HB-EGF-CTF) consisting of the transmembrane and cytoplasmic domains. We previously showed that the HB-EGF-CTF translocates from the plasma membrane to the nucleus and plays a role as a signaling molecule. Immunoprecipitation showed that HB-EGF-CTF can associate with Bcl6, a transcriptional repressor in mammalian cells. A glutathione S-transferase pulldown assay revealed that HB-EGF-CTF interacted efficiently with zinc fingers 4-6 of Bcl6. A luciferase reporter assay showed that the nuclear translocation of HB-EGF-CTF following shedding reversed transcriptional repression of cyclin D2 by Bcl6. Additionally, the level of cyclin D2 protein increased and Bcl6 interaction with the cyclin D2 promoter decreased in parallel with the shedding of pro-HB-EGF at all endogenous levels. These findings suggest that HB-EGF-CTF is a potent regulator of gene expression via its interaction with the transcriptional repressor Bcl6.
Kinugasa
Yumi
Y
Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, To-on, Ehime 791-0295, Japan.
Hieda
Miki
M
Hori
Masatsugu
M
Higashiyama
Shigeki
S
D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism*; D056742:Cyclin D2; D016213:Cyclins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D066246:ErbB Receptors / Q000819:agonists; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051560:Proto-Oncogene Proteins c-bcl-6; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*
C084103:BCL6 protein, human; C080336:CCND2 protein, human; D056742:Cyclin D2; D016213:Cyclins; D004268:DNA-Binding Proteins; C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D008024:Ligands; D010446:Peptide Fragments; D051560:Proto-Oncogene Proteins c-bcl-6; D011956:Receptors, Cell Surface; D012097:Repressor Proteins; D066246:ErbB Receptors