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Regulation of miR106b cluster through the RB pathway: Mechanismand functional targets

机译:通过RB途径调控miR106b簇的机制和功能目标

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The RB pathway plays a critical role in proliferation control that is commonly subverted in tumor development. However, restoration of RB pathway function can be elicited in many tumor cells by the inhibition of CDK4/6 activity that leads to dephosphorylation of RB and subsequent repression of E2F-mediated transcription. In this context, active RB/E2F complexes inhibit the expression of a critical program of coding genes that promote cell cycle progression. However, the non-coding RNA target genes downstream from RB that could be relevant for tumor biology remain obscure. Here, miRNA gene expression profiling identified the miR106b cluster as being efficiently repressed with CDK4/6 inhibition in an E2F and RB-dependent manner. Importantly, the miR106B-cluster is intragenic of MCM7, and through a series of functional studies, the basis of MCM7 regulation and concordant expression of the miRNA species within the 106b cluster was determined. Importantly, RB-mediated repression of the 106b cluster enhances the transcript levels of p21Cip1 and PTEN. These data provide a mechanistic basis for cross-talk between the RB pathway and p21 and PTEN through the regulation of the MCM7/miR106b locus.
机译:RB途径在通常在肿瘤发展中被破坏的增殖控制中起关键作用。但是,在许多肿瘤细胞中,通过抑制CDK4 / 6活性可导致RB通路功能的恢复,该活性导致RB的去磷酸化和随后的E2F介导的转录抑制。在这种情况下,活性RB / E2F复合物抑制了促进细胞周期进程的编码基因关键程序的表达。但是,RB下游可能与肿瘤生物学有关的非编码RNA靶基因仍然不清楚。在这里,miRNA基因表达谱鉴定出miR106b簇被CDK4 / 6抑制以E2F和RB依赖的方式有效抑制。重要的是,miR106B簇是MCM7的基因内源,并且通过一系列功能研究,确定了MCM7调控的基础和106b簇内miRNA种类的一致表达。重要的是,RB介导的106b簇的阻遏增强了p21Cip1和PTEN的转录水平。这些数据通过调节MCM7 / miR106b基因座为RB途径与p21和PTEN之间的串扰提供了机理基础。

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