Dmp53 activates the hippo pathway to promote cell death in response to DNA damage
Dmp53 activates the hippo pathway to promote cell death in response to DNA damage
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DOI：
10.1016/j.cub.2006.05.059
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发表时间：
2006-07-25
期刊：
影响因子：
9.2
通讯作者：
Tapon, Nicolas
中科院分区：
文献类型：
--
作者：
Colombani, Julien;Polesello, Cedric;Tapon, Nicolas
发育和环境信号控制着生长、增殖和细胞死亡的精确程序。该计划确保动物达到但不超过其典型大小[1]。了解细胞如何感知组织大小的极限，并通过退出细胞周期或进行增殖反应，对发育和癌症生物学都有重要意义。Hippo（Hpo）途径包括激酶Hpo和Warts/Lats（Wts）、作为肿瘤抑制因子的衔接子萨尔瓦多（Sav）和Mobl（Mats）、细胞骨架蛋白Expanded和Merlin以及转录辅因子Yorkie（Yki）[2-11]。该途径已被证明限制细胞分裂并促进细胞凋亡。半胱天冬酶阻遏物DIAP 1似乎是细胞死亡控制中Hpo途径的主要靶标。首先，Hpo促进DIAP 1磷酸化，可能降低其稳定性。其次，Wts磷酸化并使Yki失活，从而降低DIAP 1转录。尽管我们了解了Hpo激酶下游的一些事件，但其激活模式仍然是个谜。在这里，我们表明，HPO可以激活电离辐射（IR）在Dmp 53（果蝇p53）依赖的方式和HPO是必需的（虽然不是绝对的）引起的IR或Dmp 53异位表达的细胞死亡反应。
Developmental and environmental signals control a precise program of growth, proliferation, and cell death. This program ensures that animals reach, but do not exceed, their typical size [1]. Understanding how cells sense the limits of tissue size and respond accordingly by exiting the cell cycle or undergoing apoptasis has important implications for both developmental and cancer biology. The Hippo (Hpo) pathway comprises the kinases Hpo and Warts/Lats (Wts), the adaptors Salvador (Sav) and Mobl as a tumor suppressor (Mats), the cytoskeletal proteins Expanded and Merlin, and the transcriptional cofactor Yorkie (Yki) [2-11]. This pathway has been shown to restrict cell division and promote apoptosis. The caspase repressor DIAP1 appears to be a primary target of the Hpo pathway in cell-death control. Firstly, Hpo promotes DIAP1 phosphorylation, likely decreasing its stability. Secondly, Wts phosphorylates and inactivates Yki, decreasing DIAP1 transcription. Although we understand some of the events downstream of the Hpo kinase, its mode of activation remains mysterious. Here, we show that Hpo can be activated by Ionizing Radiations (IR) in a Dmp53 (Drosophila melanogaster p53)-dependent manner and that Hpo is required (though not absolutely) for the cell death response elicited by IR or Dmp53 ectopic expression.