The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration
The Hippo tumor suppressor pathway regulates intestinal stem cell regeneration
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DOI：
10.1242/dev.060483
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发表时间：
2010-12-15
期刊：
影响因子：
4.6
通讯作者：
Perrimon, Norbert
中科院分区：
文献类型：
--
作者：
Karpowicz, Phillip;Perez, Jessica;Perrimon, Norbert
识别控制干细胞（SC）增殖的信号通路，以及它们是否以细胞或非细胞自主方式起作用，是我们理解组织稳态和癌症的关键。在成年果蝇中肠中，Jun N-末端激酶（JNK）通路在损伤后受损的肠上皮细胞（EC）中被激活。这导致从EC产生Upd细胞因子，其进而激活肠SC（ISC）中的Janus激酶（JAK）/信号转导子和转录激活子（STAT）途径，刺激其增殖。此外，Hippo通路最近被认为与EC产生Upd的调节有关。在这里，我们表明，河马通路的目标，约克（Yki），也发挥了至关重要的作用，细胞自主的ISCs。ISC中Yki的激活足以增加ISC增殖，这是一个涉及促进分裂、存活和Upd细胞因子的Yki靶基因的过程。我们进一步表明，在损伤之前，Yki活性被上游Hippo通路成员Fat和Dachsous（Ds）组成性抑制。这些发现证明了Hippo通路在SC中的细胞自主作用，并对理解该通路在肿瘤发生和癌症干细胞中的作用具有意义。
Identification of the signaling pathways that control the proliferation of stem cells (SCs), and whether they act in a cell or non-cell autonomous manner, is key to our understanding of tissue homeostasis and cancer. In the adult Drosophila midgut, the Jun N-Terminal Kinase (JNK) pathway is activated in damaged enterocyte cells (ECs) following injury. This leads to the production of Upd cytokines from ECs, which in turn activate the Janus kinase (JAK)/Signal transducer and activator of transcription (STAT) pathway in Intestinal SCs (ISCs), stimulating their proliferation. In addition, the Hippo pathway has been recently implicated in the regulation of Upd production from the ECs. Here, we show that the Hippo pathway target, Yorkie (Yki), also plays a crucial and cell-autonomous role in ISCs. Activation of Yki in ISCs is sufficient to increase ISC proliferation, a process involving Yki target genes that promote division, survival and the Upd cytokines. We further show that prior to injury, Yki activity is constitutively repressed by the upstream Hippo pathway members Fat and Dachsous (Ds). These findings demonstrate a cell-autonomous role for the Hippo pathway in SCs, and have implications for understanding the role of this pathway in tumorigenesis and cancer stem cells.