title: A positive feedback loop regulates the expression of polycomb group protein BMI1 via WNT signaling pathway.
abstract: Polycomb group protein BMI1 plays an important role in cellular homeostasis by maintaining a balance between proliferation and senescence. It is often overexpressed in cancer cells and is required for self-renewal of stem cells. At present, very little is known about the signaling pathways that regulate the expression of BMI1. Here, we report that BMI1 autoactivates its own promoter via an E-box present in its promoter. We show that BMI1 acts as an activator of the WNT pathway by repressing Dickkopf (DKK) family of WNT inhibitors. BMI1 mediated repression of DKK proteins; in particular, DKK1 led to up-regulation of WNT target c-Myc, which in turn further led to transcriptional autoactivation of BMI1. Thus, a positive feedback loop connected by the WNT signaling pathway regulates BMI1 expression. This positive feedback loop regulating BMI1 expression may be relevant to the role of BMI1 in promoting cancer and maintaining stem cell phenotype.
authors.affiliation: Department of Biochemistry and Molecular Biology, The George Washington University Medical Center, Washington, DC 20037, USA.
authors.forename: Joon-Ho
authors.initials: JH
authors.lastname: Cho
authors.forename: Manjari
authors.initials: M
authors.lastname: Dimri
authors.forename: Goberdhan P
authors.initials: GP
authors.lastname: Dimri
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D002460:Cell Line; D025461:Feedback, Physiological; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D063150:Polycomb Repressive Complex 1 / Q000235:genetics* / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D015854:Up-Regulation / Q000235:genetics; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C069077:BMI1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D063146:Polycomb-Group Proteins; D016271:Proto-Oncogene Proteins c-myc; D063150:Polycomb Repressive Complex 1