Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals-猫眼课题宝

DOI：

10.1038/cr.2015.121

发表时间：

2015-10

期刊：

Cell Research

影响因子：

44.1

通讯作者：

中科院分区：

生物学1区

文献类型：

作者：

Xudong Wu;Ida Holst Bekker-Jensen;J. Christensen;K. D. Rasmussen;S. Sidoli;Yan Qi;Yu Kong;Xi Wang;Yajuan Cui;Zhijian Xiao;Guogang Xu;K. Williams;J. Rappsilber;C. Sønderby;O. Winther;O. Jensen;K. Helin

ASXL 1突变经常在血液肿瘤中发现，并且Asxl 1的缺失促进小鼠的骨髓转化。在这里，我们提出的数据支持的作用ASXL 1-BAP 1复合物在去泛素化的单泛素化的赖氨酸119组蛋白H2 A（H2 AK 119 ub 1）在体内。Polycomb组蛋白在正常发育期间控制INK 4 B-ARF-INK 4A基因座的表达，部分通过催化H2 AK 119的单泛素化。由于INK 4 B-ARF-INK 4A位点的激活起着防止肿瘤发生的故障安全机制，我们研究了ASXL 1依赖性H2 A去泛素化是否在其激活中起作用。有趣的是，我们发现ASXL 1是p15 INK 4 B表达增加所必需的，以响应致癌信号和外源性抗增殖信号。由于我们发现ASXL 1和BAP 1都富集在INK 4 B位点，我们的研究结果表明，INK 4 B位点的激活需要ASXL 1/BAP 1介导的H2 AK 119 ub 1去泛素化。因此，我们的研究结果表明，ASXL 1突变与p15 INK 4 B的表达水平较低和造血祖细胞在原代骨髓细胞中的增殖优势相关，并且ASXL 1在多个细胞系中的缺失导致对生长抑制信号的抗性。总之，这项研究将ASXL 1介导的H2 A去泛素化和INK 4 B表达的转录激活与其肿瘤抑制功能联系起来。

ASXL1 mutations are frequently found in hematological tumors, and loss of Asxl1 promotes myeloid transformation in mice. Here we present data supporting a role for an ASXL1-BAP1 complex in the deubiquitylation of mono-ubiquitylated lysine 119 on Histone H2A (H2AK119ub1) in vivo. The Polycomb group proteins control the expression of the INK4B-ARF-INK4A locus during normal development, in part through catalyzing mono-ubiquitylation of H2AK119. Since the activation of the locus INK4B-ARF-INK4A plays a fail-safe mechanism protecting against tumorigenesis, we investigated whether ASXL1-dependent H2A deubiquitylation plays a role in its activation. Interestingly, we found that ASXL1 is specifically required for the increased expression of p15 INK4B in response to both oncogenic signaling and extrinsic anti-proliferative signals. Since we found that ASXL1 and BAP1 both are enriched at the INK4B locus, our results suggest that activation of the INK4B locus requires ASXL1/BAP1-mediated deubiquitylation of H2AK119ub1. Consistently, our results show that ASXL1 mutations are associated with lower expression levels of p15 INK4B and a proliferative advantage of hematopoietic progenitors in primary bone marrow cells, and that depletion of ASXL1 in multiple cell lines results in resistance to growth inhibitory signals. Taken together, this study links ASXL1-mediated H2A deubiquitylation and transcriptional activation of INK4B expression to its tumor suppressor functions.

Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals

文献摘要

相似文献