Instituto de Investigaciones Biomédicas CSIC-UAM, Madrid, Spain.
Cancer Res. 2010 Mar 1;70(5):1866-74. doi: 10.1158/0008-5472.CAN-09-2088. Epub 2010 Feb 23.
The ING family of tumor suppressor proteins controls several cellular functions relevant to antitumor protection, such as cell cycle control, apoptosis, senescence, or migration. ING proteins are functionally linked to the p53 pathway, and they participate in transcriptional control via the recognition of histone marks and recruitment of protein complexes with chromatin-modifying activity to specific promoters. Here, we have investigated the global effect of ING1 in gene regulation through genome-wide analysis of expression profiles in primary embryonic fibroblasts deficient for the Ing1 locus. We find that Ing1 has a predominant role as transcriptional repressor in this setting, affecting the expression of genes involved in a variety of cellular functions. Within the subset of genes showing differential expression, we have identified DGCR8, a protein involved in the early steps of microRNA biogenesis. We show that ING1 binds to the DGCR8 promoter and controls its transcription through chromatin regulation. We also find that ING1 and DGCR8 can cooperate in restraining proliferation. In summary, this study reveals a novel connection between ING1 and a regulator of microRNA biogenesis and identifies new links between tumor suppressor proteins and the microRNA machinery.
ING 家族的肿瘤抑制蛋白控制着几种与抗肿瘤保护相关的细胞功能,如细胞周期控制、细胞凋亡、衰老或迁移。ING 蛋白与 p53 途径在功能上相关联,它们通过识别组蛋白标记和募集具有染色质修饰活性的蛋白质复合物到特定启动子来参与转录控制。在这里,我们通过对缺乏 Ing1 基因座的原代胚胎成纤维细胞的表达谱进行全基因组分析,研究了 ING1 在基因调控中的全局效应。我们发现,在这种情况下,Ing1 主要作为转录抑制因子发挥作用,影响参与各种细胞功能的基因的表达。在显示差异表达的基因子集内,我们鉴定了 DGCR8,这是一种参与 microRNA 生物发生早期步骤的蛋白质。我们表明,ING1 结合到 DGCR8 启动子并通过染色质调节控制其转录。我们还发现 ING1 和 DGCR8 可以合作抑制增殖。总之,这项研究揭示了 ING1 与 microRNA 生物发生调节剂之间的新联系,并确定了肿瘤抑制蛋白与 microRNA 机制之间的新联系。