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.
Highlights
Polycomb group (PcG) protein BMI1 is transcriptionally regulated by Myc and is up-regulated in cancer cells
BMI1 Expression Inversely Correlates with Expression of DKK Family of Proteins in Breast Cancer Cells—As our array data suggested that BMI1 may repress WNT inhibitors, in particular the DKK family of proteins, and BMI1 is known to be overexpressed in many breast cancer cell lines, we examined whether there is an inverse correlation between the expression of BMI1 and DKK1, DKK2, and DKK3 in breast cancer cells
BMI1 Transcriptionally Regulates DKK1—we focused on the potential mechanism of regulation of the WNT pathway by BMI1
Summary
PcG protein BMI1 is transcriptionally regulated by Myc and is up-regulated in cancer cells. Results: The WNT pathway plays an important role in Myc regulation of BMI1. 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. Despite its well documented role in cellular senescence, cancer, and stem cell phenotype, at present, very little is known about the regulation of BMI1. Set 4 (Ϫ140, ϩ155) (F) 5Ј-ATGCTCCGGGCCCGCGGTAT-3Ј (R) 5Ј-GTGGCGCTCACTCCCAGCAG-3Ј regulation of the WNT pathway and expression of DKK1, DKK2, and DKK3 by BMI1. We report that BMI1 negatively regulates expression of these DKK family members, in particular DKK1, and that their negative regulation results in up-regulation of WNT targets such as c-Myc that participate in a positive feedback loop, activating transcription of BMI1 gene via an E-box present in its promoter
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