High mobility group A1 protein modulates autophagy in cancer cells.
High mobility group A1 protein modulates autophagy in cancer cells.
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DOI：
10.1038/cdd.2017.117
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发表时间：
2017-11
影响因子：
12.4
通讯作者：
Pierantoni GM
中科院分区：
文献类型：
--
作者：
Conte A;Paladino S;Bianco G;Fasano D;Gerlini R;Tornincasa M;Renna M;Fusco A;Tramontano D;Pierantoni GM
高迁移率族A1（HMGA 1）是一种结构性染色质蛋白，其过表达是恶性肿瘤的一个特征，在癌症的发生和发展中起着因果作用。HMGA 1通过多种机制促进肿瘤生长，包括增加细胞增殖和存活、损伤DNA修复和诱导染色体不稳定性。自噬是一种自我降解的过程，通过提供能量来源和去除受损的细胞器和错误折叠的蛋白质，使细胞在应激条件下存活。另一方面，过度激活的自噬可导致非凋亡的程序性细胞死亡。自噬失调是癌细胞的共同特征，在其中具有复杂的作用，根据细胞背景和肿瘤阶段显示致癌或肿瘤抑制活性。在这里，我们报告说，耗尽HMGA 1干扰自噬通过不同的机制。HMGA 1敲低通过抑制mTOR通路（自噬的主要调节因子）的活性和转录上调自噬起始激酶Unc-51样激酶1（ULK 1）来增加自噬体形成。因此，功能实验证明HMGA 1结合ULK 1启动子区并负调控其转录。另一方面，自噬体的增加与其成熟的成比例增加无关。总的来说，HMGA 1耗竭对自噬的影响与细胞增殖的减少相关，并最终影响癌细胞的活力。重要的是，ULK 1的沉默阻止了HMGA 1敲低对细胞增殖、活力和自噬活性的影响，突出了这些影响至少部分是由ULK 1介导的。有趣的是，这种现象并不局限于皮肤癌细胞，因为在HMGA 1沉默的HeLa细胞中也观察到了类似的结果。总之，这些结果清楚地表明HMGA 1是癌细胞自噬途径的关键调节因子，从而表明HMGA 1可以促进癌症进展的新机制。
High Mobility Group A1 (HMGA1) is an architectural chromatin protein whose overexpression is a feature of malignant neoplasias with a causal role in cancer initiation and progression. HMGA1 promotes tumor growth by several mechanisms, including increase of cell proliferation and survival, impairment of DNA repair and induction of chromosome instability. Autophagy is a self-degradative process that, by providing energy sources and removing damaged organelles and misfolded proteins, allows cell survival under stress conditions. On the other hand, hyper-activated autophagy can lead to non-apoptotic programmed cell death. Autophagy deregulation is a common feature of cancer cells in which has a complex role, showing either an oncogenic or tumor suppressor activity, depending on cellular context and tumor stage. Here, we report that depletion of HMGA1 perturbs autophagy by different mechanisms. HMGA1-knockdown increases autophagosome formation by constraining the activity of the mTOR pathway, a major regulator of autophagy, and transcriptionally upregulating the autophagy-initiating kinase Unc-51-like kinase 1 (ULK1). Consistently, functional experiments demonstrate that HMGA1 binds ULK1 promoter region and negatively regulates its transcription. On the other hand, the increase in autophagosomes is not associated to a proportionate increase in their maturation. Overall, the effects of HMGA1 depletion on autophagy are associated to a decrease in cell proliferation and ultimately impact on cancer cells viability. Importantly, silencing of ULK1 prevents the effects of HMGA1-knockdown on cellular proliferation, viability and autophagic activity, highlighting how these effects are, at least in part, mediated by ULK1. Interestingly, this phenomenon is not restricted to skin cancer cells, as similar results have been observed also in HeLa cells silenced for HMGA1. Taken together, these results clearly indicate HMGA1 as a key regulator of the autophagic pathway in cancer cells, thus suggesting a novel mechanism through which HMGA1 can contribute to cancer progression.
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影响因子：
4.8
作者：
Jain, Ashish;Lamark, Trond;Johansen, Terje
通讯作者：
Johansen, Terje
DOI：
10.1038/nrm3735
发表时间：
2014-02
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
--
细胞死亡的基本与附件方面：NCCD 2015的建议。
影响因子：
12.4
作者：
通讯作者：
--
影响因子：
16
作者：
Joo JH;Wang B;Frankel E;Ge L;Xu L;Iyengar R;Li-Harms X;Wright C;Shaw TI;Lindsten T;Green DR;Peng J;Hendershot LM;Kilic F;Sze JY;Audhya A;Kundu M
通讯作者：
Kundu M
影响因子：
2.4
作者：
Federico A;Forzati F;Esposito F;Arra C;Palma G;Barbieri A;Palmieri D;Fedele M;Pierantoni GM;De Martino I;Fusco A
通讯作者：
Fusco A