Destabilization of RAG proteins and cell cycle regulation by Polycomb group genes

在果蝇中，Polycomb group(PcG)基因通过染色质沉默被认为是转录记忆机制的负调节基因。它们确保了关键调控基因的转录模式的维持，如同源异型基因，这些基因参与了身体计划的口述，但其他功能和靶基因至今还没有得到很好的研究。MEL-18是果蝇PcG基因在哺乳动物中的同源物，是果蝇PcG基因的后性梳理和编码转录抑制因子，具有肿瘤抑制活性。在这里，我们发现过度表达Mel-18的小鼠表现出成熟B细胞在B细胞受体(BCR)刺激下的细胞周期停滞，c-myc下调。分子分析表明，细胞周期蛋白D2、细胞周期蛋白E、细胞周期蛋白4、细胞周期蛋白6、细胞周期蛋白7和细胞周期蛋白25A的表达下调，导致细胞周期蛋白依赖性蛋白的活性降低，从而导致视网膜母细胞瘤蛋白的低磷酸化。反之，c-myc、CDC25和CDC2/CDK2激酶活性上调导致MEL-18缺陷小鼠B细胞增殖增强。C-Myc对cdc25a的表达有正向调节作用。因此，我们认为MEL-18至少通过导致c-myc和cdc25a的级联反应负向调节细胞周期进程。我们还将讨论Mel-18缺陷小鼠的淋巴细胞发育缺陷暗示Mel-18通过调节其对细胞死亡的易感性而参与了未成熟淋巴细胞的维持。最近，我们在老年Mel-18+/-小鼠中发现了自发的肿瘤发生。因此，我们认为PcG基因是控制淋巴样细胞增殖和死亡之间平衡的调节者，从而在免疫性疾病的预防、诊断和治疗中具有应用前景。

Polycomb group (PcG) genes are known as negative regulators of the transcriptional memory mechanisms via chromatin silencing in Drosophila. They ensure the maintenance of transcription patterns of key regulators such as homeotic genes which were involved in the dictation of body plan, however the other functions and target genes were not well investigated to date. mel-18 is a mammalian homologue of Drosophila PcG gene posterior sex combs and encodes a transcriptional repressor with tumor suppressive activity. Here we found that mice overexpressing mel-18 showed a cell cycle arrest of mature B-cells on B-cell receptor (BCR) stimulation with downregulation of c-myc. Molecular analysis revealed that the downregulation of cyclinD2, cyclinE, CDK4, CDK6 , CDK7, and CDC25A causes the impaired activities of cyclin-dependent kinases, resulting in hypophosphorylation of the retinoblastoma protein. Vise versa, the upregulation of c-MYC, CDC25 and CDC2/CDK2 kinase activities resulted in augmentation of proliferation of B-cells in mel-18 deficient mice. c-Myc is known to regulate positively the expression of cdc25a. Thus we propose that mel-18 negatively regulates the cell cycle progression at least through a cascades leading to c-myc then cdc25a. We will also discuss that the defect in lymphocyte development of mel-18 deficient mice implies the involvement of mel-18 in the maintenance of immature lymphocyte by regulating their susceptibility to cell death. More recently we found the spontaneous tumorigenesis in aged mel-18+/- mice. Therefore we would like to propose that PcG genes are the regulators to control the balance between proliferation and cell deathin lympoid cell, hence in prospects of applications to prevention, diagnosis and therapy of immunological disease.