A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development.
A Non-Cell-Autonomous Role of BEC-1/BECN1/Beclin1 in Coordinating Cell-Cycle Progression and Stem Cell Proliferation during Germline Development.
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DOI：
10.1016/j.cub.2017.02.015
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发表时间：
2017-03-20
期刊：
影响因子：
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通讯作者：
Meléndez A
中科院分区：
文献类型：
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作者：
Ames K;Da Cunha DS;Gonzalez B;Konta M;Lin F;Shechter G;Starikov L;Wong S;Bülow HE;Meléndez A
干细胞增殖和分化的决定受到精细控制。秀丽隐杆线虫生殖系为研究控制干细胞增殖和体内平衡的机制提供了一个易处理的系统。自噬是一种保守的细胞再循环过程，在许多不同的情况下对细胞内稳态至关重要，但其在生殖系干细胞增殖中的功能仍然知之甚少。在这里，我们描述了生殖系干细胞增殖中自噬的功能。我们发现自噬基因如bec-1/Beclin 1、atg-16.2/ATG 16 L、atg-18/WIPI 1/2和atg-7/ATG 7等是C.秀丽隐翅虫性腺我们进一步表明，BEC-1/Beclin 1独立于GLP-1/Notch或TGF-β 7/TGFβ通路发挥作用，但与GLP-2/胰岛素IGF-1受体（IIR）信号通路一起促进生殖系干细胞增殖。BEC-1/Beclin 1、ATG-18/WIPI 1/2和ATG-16.2/ATG-16 L与Bcl-2/IIR相似，均能促进细胞周期进程，并受磷酸酶和张力蛋白Bcl-18/PTEN的负调控。然而，BEC-1/Beclin 1通过转录调节因子SKN-1/Nrf 1发挥作用，而ATG-18/WIPI 1/2和ATG-16.2/ATG 16 L则通过转录因子SKN-16/FOXO发挥作用。相比之下，ATG-7与TGF-7/ TGFβ通路协同作用以促进生殖系增殖，并且不是细胞周期进展所必需的。最后，我们报告说，BEC-1/Beclin 1功能细胞非自主地促进细胞周期的进展和干细胞增殖。我们的研究结果表明BEC-1/Beclin 1在控制干细胞增殖和细胞周期进程中具有新型的非自主作用，这可能对未来针对恶性细胞生长的疗法的理解和开发具有影响。
The decision of stem cells to proliferate and differentiate is finely controlled. The Caenorhabditis elegans germ line provides a tractable system to study the mechanisms that control stem cell proliferation and homeostasis. Autophagy is a conserved cellular recycling process crucial for cellular homeostasis in many different contexts, but its function in germline stem cell proliferation remains poorly understood. Here, we describe a function for autophagy in germline stem cell proliferation. We found that autophagy genes, such as bec-1/Beclin1, atg-16.2/ATG16L, atg-18/WIPI1/2, and atg-7/ATG7 are required for the late larval expansion of germline stem cell progenitors in the C. elegans gonad. We further show that BEC-1/Beclin1 acts independently of the GLP-1/Notch or DAF-7/TGFβ pathways, but together with the DAF-2/insulin IGF-1 receptor (IIR) signaling pathway to promote germline stem cell proliferation. Similar to DAF-2/IIR, BEC-1/Beclin1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L all promote cell cycle progression, and are negatively regulated by the phosphatase and tensin DAF-18/PTEN. However, whereas BEC-1/Beclin1 acts through the transcriptional regulator SKN-1/Nrf1, ATG-18/WIPI1/2 and ATG-16.2/ATG16L exert their function through the DAF-16/FOXO transcription factor. In contrast, ATG-7 functions in concert with the DAF-7/ TGFβ pathway to promote germline proliferation, and is not required for cell cycle progression. Finally, we report that BEC-1/Beclin1 functions cell non-autonomously to facilitate cell cycle progression and stem cell proliferation. Our findings demonstrate a novel non-autonomous role for BEC-1/Beclin1 in the control stem cell proliferation, and cell cycle progression, which may have implications for the understanding, and development, of therapies against malignant cell growth in the future.