An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia.
An intergenic regulatory region mediates Drosophila Myc-induced apoptosis and blocks tissue hyperplasia.
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作者：
在脊椎动物中，癌基因诱导的过度增殖后诱导细胞自主凋亡是一种主要的肿瘤抑制机制。然而，这一过程的详细机制仍然是个谜。在这项研究中，我们证明，dMyc诱导的细胞自主凋亡的果蝇果蝇依赖于一个基因间序列称为IRER（辐射响应增强区）。IRER介导周围促凋亡基因的表达，我们使用IRER染色质状态的体内报告来收集证据，证明IRER内DNA可及性的表观遗传控制是这种对过量dMyc反应强度的重要决定因素。在先前的工作中，我们发现IRER也介导DNA损伤后促凋亡基因的P53依赖性诱导，并且IRER内的染色质构象受Polycomb组介导的组蛋白修饰的调节。因此，dMyc诱导的细胞凋亡和P53介导的DNA损伤反应在IRER的需求中重叠。控制IRER可及性的表观遗传机制似乎为体内P53和dMyc诱导的凋亡基因表达设定了阈值，并可能对细胞对癌基因诱导的应激的敏感性产生深远影响。
Induction of cell autonomous apoptosis following oncogene-induced overproliferation is a major tumor-suppressive mechanism in vertebrates. However the detailed mechanism mediating this process remains enigmatic. In this study we demonstrate that dMyc-induced cell-autonomous apoptosis in the fruit fly Drosophila melanogaster relies on an intergenic sequence termed the IRER (Irradiation Responsive Enhancer Region). The IRER mediates expression of surrounding pro-apoptotic genes, and we use an in vivo reporter of the IRER chromatin state to gather evidence that epigenetic control of DNA accessibility within the IRER is an important determinant of the strength of this response to excess dMyc. In prior work we showed that the IRER also mediates P53-dependent induction of pro-apoptotic genes following DNA damage, and the chromatin conformation within IRER is regulated by Polycomb group-mediated histone modifications. dMyc-induced apoptosis and the P53-mediated DNA damage response thus overlap in a requirement for the IRER. The epigenetic mechanisms controlling IRER accessibility appear to set thresholds for the P53 and dMyc-induced expression of apoptotic genes in vivo and may have a profound impact on cellular sensitivity to oncogene-induced stress.
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影响因子：
64.8
作者：
STRASSER, A;HARRIS, AW;CORY, S
通讯作者：
CORY, S
影响因子：
64.5
作者：
Pelengaris, S;Khan, M;Evan, GI
通讯作者：
Evan, GI
影响因子：
7
作者：
Kikuta, Hiroshi;Laplante, Mary;Becker, Thomas S.
通讯作者：
Becker, Thomas S.
影响因子：
56.9
作者：
Venken, Koen J. T.;He, Yuchun;Bellen, Hugo J.
通讯作者：
Bellen, Hugo J.
DOI：
10.1073/pnas.0535280100
发表时间：
2003-03-04
影响因子：
11.1
作者：
Gong, WJ;Golic, KG
通讯作者：
Golic, KG