RUNX3 表达和活性的调控
中文名称
通路描述
RUNX3 与其他 RUNX 家族成员一样，由两个启动子转录：近端 P2 启动子和远端 P1 启动子。P2 启动子位于一个大的 CpG 岛中，该岛在实体瘤中频繁甲基化，导致 RUNX3 基因的表观遗传失活 (reviewed by Levanon and Groner 2004)。RUNX3 的转录受 SMAD4 水平的影响。RUNX3 可能通过正反馈循环直接上调其自身的转录 (Whittle et al. 2015)。在缺氧条件下，RUNX3 的转录被下调。缺氧下 RUNX3 的沉默涉及缺氧诱导的组蛋白甲基转移酶 G9a 和组蛋白去乙酰化酶 HDAC1 的上调，这导致组蛋白 H3 在赖氨酸残基 K9 (考虑起始甲硫氨酸为 K10) 处增加二甲基化，并减少组蛋白 H3 在 RUNX3 启动子处的乙酰化 (Lee et al. 2009)。RUNX3 蛋白水平与 microRNA miR-130b 水平成反比。基于计算分析，RUNX3 被预测为 miR-130b 的靶基因，但尚未通过结合实验和 3'UTR 报告实验证实 (Lai et al. 2010, Paudel et al. 2016)。与 RUNX1 和 RUNX2 类似，RUNX3 与 CBFB (CBF-beta) 形成具有转录活性的异二聚体 (Kim et al. 2013)。RUNX3 活性可通过 RUNX3 定位的变化进行调控。SRC 蛋白酪氨酸激酶在 RUNX3 的多个酪氨酸残基上磷酸化，抑制其从细胞质转位至细胞核，从而抑制 RUNX3 介导的转录 (Goh et al. 2010)。RUNX3 的亚细胞定位可能受 PIM1 介导的磷酸化影响 (Kim et al. 2008)。P1 和 P2 启动子以细胞类型/分化依赖性方式调控 RUNX3 的转录，分别产生 p44 和 p46 型 RUNX3。已报道多种剪接异构体。一个例子是通过剪接产生 33 kDa 蛋白异构体 (p33)。p33 异构体缺乏 Runt 结构域，无法激活整合素基因的调控区域。p33 异构体在单核来源树突状细胞 (MDDC) 成熟过程中诱导，导致炎症反应相关基因（如 IL8，即白细胞介素 -8）表达降低 (Puig-Kroger et al. 2010)。E3 泛素连接酶 MDM2 (Chi et al. 2009)、SMURF1 和 SMURF2 (Jin et al. 2004) 参与 RUNX3 多泛素化和降解。
英文描述
Regulation of RUNX3 expression and activity RUNX3, like other RUNX family members, is transcribed from two promoters - the proximal P2 promoter and the distal P1 promoter. The P2 promoter is positioned within a large CpG island that is frequently methylated in solid tumors, resulting in epigenetic inactivation of the RUNX3 gene (reviewed by Levanon and Groner 2004). RUNX3 transcription is affected by SMAD4 levels. RUNX3 may directly upregulate its own transcription through a positive feedback loop (Whittle et al. 2015). Under hypoxic conditions, RUNX3 transcription is downregulated. Hypoxic silencing of RUNX3 involves hypoxia-induced upregulation of the histone methyltransferase G9a and histone deacetylase HDAC1, which leads to increased dimethylation of histone H3 at lysine residue K9 (K10 when taking into account the initiator methionine) and reduced acetylation of histone H3 at the RUNX3 promoter (Lee et al. 2009).
RUNX3 protein levels are inversely related to the levels of microRNA miR-130b. Based on in silico analysis, RUNX3 is predicted to be the target of miR-130b, but binding assays and 3'UTR reporter assays have not been done to confirm this (Lai et al. 2010, Paudel et al. 2016).
Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta) (Kim et al. 2013). RUNX3 activity can be regulated by changes in RUNX3 localization. SRC protein tyrosine kinase phosphorylates RUNX3 on multiple tyrosine residues, inhibiting its translocation from the cytosol to the nucleus and thus inhibiting RUNX3-mediated transcription (Goh et al. 2010). Subcellular localization of RUNX3 may be affected by PIM1-mediated phosphorylation (Kim et al. 2008).
The P1 and P2 promoters regulate RUNX3 transcription in a cell-type/differentiation dependent manner, giving rise to the p44 and p46 isoforms of RUNX3, respectively. Several splicing isoforms have also been reported. One example is the generation of a 33 kDa protein isoform (p33) by alternative splicing. The RUNX3 p33 isoform lacks the Runt domain and is unable to transactivate the regulatory regions of integrin genes. The p33 isoform is induced during maturation of monocyte-derived dendritic cells (MDDC), leading to reduced expression of genes involved in inflammatory responses, such as IL8 (interleukin-8) (Puig-Kroger et al. 2010).
E3 ubiquitin ligases MDM2 (Chi et al. 2009), SMURF1 and SMURF2 (Jin et al. 2004) are implicated in RUNX3 polyubiquitination and degradation.
RUNX3 protein levels are inversely related to the levels of microRNA miR-130b. Based on in silico analysis, RUNX3 is predicted to be the target of miR-130b, but binding assays and 3'UTR reporter assays have not been done to confirm this (Lai et al. 2010, Paudel et al. 2016).
Similar to RUNX1 and RUNX2, RUNX3 forms a transcriptionally active heterodimer with CBFB (CBF-beta) (Kim et al. 2013). RUNX3 activity can be regulated by changes in RUNX3 localization. SRC protein tyrosine kinase phosphorylates RUNX3 on multiple tyrosine residues, inhibiting its translocation from the cytosol to the nucleus and thus inhibiting RUNX3-mediated transcription (Goh et al. 2010). Subcellular localization of RUNX3 may be affected by PIM1-mediated phosphorylation (Kim et al. 2008).
The P1 and P2 promoters regulate RUNX3 transcription in a cell-type/differentiation dependent manner, giving rise to the p44 and p46 isoforms of RUNX3, respectively. Several splicing isoforms have also been reported. One example is the generation of a 33 kDa protein isoform (p33) by alternative splicing. The RUNX3 p33 isoform lacks the Runt domain and is unable to transactivate the regulatory regions of integrin genes. The p33 isoform is induced during maturation of monocyte-derived dendritic cells (MDDC), leading to reduced expression of genes involved in inflammatory responses, such as IL8 (interleukin-8) (Puig-Kroger et al. 2010).
E3 ubiquitin ligases MDM2 (Chi et al. 2009), SMURF1 and SMURF2 (Jin et al. 2004) are implicated in RUNX3 polyubiquitination and degradation.
所含基因
44 个基因