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

Polycomb group （PcG）基因被认为是通过果蝇染色质沉默介导转录记忆机制的负调控因子。它们确保了关键调控因子的转录模式的维持，如参与身体计划决定的同型基因，但其他功能和靶基因迄今尚未得到很好的研究。mel-18是果蝇后性梳PcG基因的哺乳动物同源基因，编码一种具有肿瘤抑制活性的转录抑制因子。我们发现过表达mel-18的小鼠在b细胞受体（BCR）刺激下成熟b细胞的细胞周期阻滞，c-myc下调。分子分析显示，cyclinD2、cyclinE、CDK4、CDK6、CDK7和CDC25A的下调导致细胞周期蛋白依赖性激酶活性受损，导致视网膜母细胞瘤蛋白的低磷酸化。反之，在mel-18缺陷小鼠中，c-MYC、CDC25和CDC2/CDK2激酶活性上调导致b细胞增殖增强。已知c-Myc积极调节cdc25a的表达。因此，我们提出mel-18至少通过级联导致c-myc和cdc25a负性调节细胞周期进程。我们还将讨论mel-18缺陷小鼠淋巴细胞发育的缺陷，这意味着mel-18通过调节未成熟淋巴细胞对细胞死亡的易感性参与了淋巴细胞的维持。最近，我们在老年mel-18+/-小鼠中发现了自发肿瘤发生。因此，我们认为PcG基因是控制淋巴细胞增殖与死亡平衡的调节因子，在免疫疾病的预防、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.