A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway
A Positive Feedback Loop Regulates the Expression of Polycomb Group Protein BMI1 via WNT Signaling Pathway
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DOI：
10.1074/jbc.m112.422931
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发表时间：
2013-02-01
影响因子：
4.8
通讯作者：
Dimri, Goberdhan P.
中科院分区：
文献类型：
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作者：
Cho, Joon-Ho;Dimri, Manjari;Dimri, Goberdhan P.
Polycomb group蛋白BMI1通过维持细胞增殖和衰老之间的平衡，在细胞稳态中起重要作用。它经常在癌细胞中过度表达，是干细胞自我更新所必需的。目前，对BMI1表达调控的信号通路知之甚少。在这里，我们报告BMI1通过其启动子中的E-box自动激活其自身的启动子。我们发现BMI1通过抑制Dickkopf （DKK）家族的WNT抑制剂，作为WNT通路的激活剂。BMI1介导的DKK蛋白抑制；特别是，DKK1导致WNT靶点c-Myc上调，进而进一步导致BMI1的转录自激活。因此，由WNT信号通路连接的正反馈回路调节BMI1的表达。这种调节BMI1表达的正反馈回路可能与BMI1在促进癌症和维持干细胞表型中的作用有关。
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.