Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine
Src kinase function controls progenitor cell pools during regeneration and tumor onset in the Drosophila intestine
复制标题
DOI：
10.1038/onc.2014.163
复制
发表时间：
2015-04-30
期刊：
影响因子：
8
通讯作者：
Edgar, B. A.
中科院分区：
文献类型：
--
作者：
Kohlmaier, A.;Fassnacht, C.;Edgar, B. A.
Src非受体激酶与肿瘤进展晚期事件有关。在这里，我们研究Src激酶在果蝇肠干细胞（ISC）谱系中的作用，在组织稳态和肿瘤发病。成年果蝇的肠道仅含有两种祖细胞类型，即具有分裂能力的ISC及其后代，即有丝分裂后肠母细胞（EB）。我们发现果蝇Src 42 a和Src 64 b是最佳再生ISC分裂所必需的。相反，Src 42 a、Src 64 b或另一种非受体激酶Ack的激活通过协同刺激G1/S和G2/M细胞周期进程促进静止ISCs的分裂。由于细胞因子受体非依赖性Stat 92 E激活，延长的Src激酶激活导致组织过度生长。这不是由于ISC的对称分裂增加，而是涉及弱特异性Notch（+）但具有分裂能力的EB样细胞的积累。Src激活触发了由String/Cdc 25和Cyclin E组成的促有丝分裂模块的表达，该模块足以引起不仅ISC而且EB的分裂。在野生型中还发现了一小部分具有类似分裂能力的转运放大Notch（+）EB。在野生型中没有强烈表现出其过渡扩增潜力的中间细胞类型的扩增也可能有助于其他生物体中其他组织的再生生长和肿瘤发展。
Src non-receptor kinases have been implicated in events late in tumor progression. Here, we study the role of Src kinases in the Drosophila intestinal stem cell (ISC) lineage, during tissue homeostasis and tumor onset. The adult Drosophila intestine contains only two progenitor cell types, division-capable ISCs and their daughters, postmitotic enteroblasts (EBs). We found that Drosophila Src42a and Src64b were required for optimal regenerative ISC division. Conversely, activation of Src42a, Src64b or another nonreceptor kinase, Ack, promoted division of quiescent ISCs by coordinately stimulating G1/S and G2/M cell cycle phase progression. Prolonged Src kinase activation caused tissue overgrowth owing to cytokine receptor-independent Stat92E activation. This was not due to increased symmetric division of ISCs, but involved accumulation of weakly specified Notch(+) but division-capable EB-like cells. Src activation triggered expression of a mitogenic module consisting of String/Cdc25 and Cyclin E that was sufficient to elicit division not only of ISCs but also of EBs. A small pool of similarly division-capable transit-amplifying Notch(+) EBs was also identified in the wild type. Expansion of intermediate cell types that do not robustly manifest their transit-amplifying potential in the wild type may also contribute to regenerative growth and tumor development in other tissues in other organisms.