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

多梳组基因（Polycomb group，PcG）是果蝇中通过染色质沉默实现转录记忆机制的负调控基因。它们确保了参与体平面决定的同源异型基因等关键调控因子的转录模式的维持，但迄今为止，对其他功能和靶基因的研究还不够深入。mel-18是果蝇PcG基因后性梳的哺乳动物同源物，编码具有肿瘤抑制活性的转录抑制因子。在此，我们发现过表达mel-18的小鼠在B细胞受体（BCR）刺激下表现出成熟B细胞的细胞周期停滞，并伴有c-myc的下调。分子分析表明，细胞周期蛋白D2、细胞周期蛋白E、CDK 4、CDK 6、CDK 7和CDC 25 A的下调会导致细胞周期蛋白依赖性激酶的活性受损，从而导致视网膜母细胞瘤蛋白的低磷酸化。反之亦然，c-MYC、CDC 25和CDC 2/CDK 2激酶活性的上调导致mel-18缺陷小鼠中B细胞增殖的增强。已知c-Myc正向调节cdc 25 a的表达。因此，我们认为mel-18至少通过c-myc和cdc 25 a的级联反应负调控细胞周期进程。我们还将讨论mel-18缺陷小鼠淋巴细胞发育的缺陷意味着mel-18通过调节未成熟淋巴细胞对细胞死亡的敏感性参与维持未成熟淋巴细胞。最近，我们发现自发性肿瘤发生在老年mel-18+/-小鼠。因此，我们认为PcG基因是类胶质细胞增殖与死亡平衡的调节因子，在免疫性疾病的预防、诊断和治疗中具有广阔的应用前景。

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.