Turning an old GADDget into a troublemaker.
Turning an old GADDget into a troublemaker.
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DOI：
10.1038/s41418-018-0087-6
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发表时间：
2018-03
影响因子：
12.4
通讯作者：
Franzoso G
中科院分区：
文献类型：
--
作者：
Capece D;D'Andrea D;Verzella D;Tornatore L;Begalli F;Bennett J;Zazzeroni F;Franzoso G
生命必须不断抵御感染。最古老的免疫类型之一是主动细胞死亡的过程，它首先出现在原生生物的进化中，作为对抗细胞内寄生虫的原始防御。由于这种共同的祖先起源，在细胞凋亡途径和炎症途径之间的蛋白质、信号复合物和结构域中存在显著的对称性和重叠。这种相互联系和重叠的最清楚的范例是半胱天冬酶家族蛋白酶，其可以发出细胞死亡或促炎细胞因子激活的信号，以及NF-κ B家族转录因子，其是脊椎动物和无脊椎动物中普遍存在的快速反应系统，主要参与细胞凋亡和免疫及炎症反应的调节[1]。鉴于其在疾病发病机制中的核心作用，这些途径的基础机制具有重要的临床意义。值得注意的是，在许多癌症类型中，细胞凋亡和炎症的正常紧密调节经常被异常的NF-κB活化破坏[2]。虽然多种控制机制通常确保生理性NF-κB信号传导的迅速停止，但在大多数人类癌症中，许多改变组成性地激活NF-κB，使其能够通过调节抑制癌细胞凋亡和协调肿瘤微环境（TME）中的炎症的基因来促进肿瘤进展、转移性传播和治疗抗性，从而劫持了细胞凋亡和炎症途径之间的古老联系[2，3]。尽管进行了大量的研究，但NF-κB介导这些功能的机制仍不完全清楚。最近，我们加深了他们对多发性骨髓瘤的理解，多发性骨髓瘤是一种浆细胞依赖于NF-κB活化而存活的癌症。我们发现，致癌NF-κB信号通过上调其促生存靶基因GADD 45 B（GADD 45基因家族的成员）介导这种效应。因此，GADD 45 β在大多数多发性骨髓瘤中高度表达，其通过抑制JNK激酶MKK 7来抑制自发JNK/MAPK途径激活引起的细胞凋亡[4]。除了阻断癌细胞凋亡外，致癌NF-κB信号传导在TME中起作用，从而将癌症与炎症联系起来[3]。非恶性肿瘤相关细胞（尤其是髓系细胞）中的NF-κB活化已被证明可增强细胞因子和其他促进肿瘤细胞增殖、组织侵袭和治疗耐药性的特异性效应物的产生，同时抑制抗肿瘤免疫应答[5]。然而，NF-κB在恶性细胞和TME中通过完全不同的基因集介导其致癌功能的观点，其抑制细胞凋亡或控制炎症，与这些过程的整体结构保守和共同进化不一致。但事实证明，事实并非如此[6]。我们确定了一个由GADD 45 β介导的NF-κB B通路的专用轴，它整合了NF-κ B依赖性机制，抑制肿瘤细胞增殖，
Life must continually defend against infection. One of the most ancient types of immunity is the process of active cell death, which first arose in evolution plausibly with protists, as a primordial defence against intracellular parasites. Owing to this common ancestral origin, there is remarkable symmetry and overlap in proteins, signalling complexes and domains between the pathways of apoptosis and those of inflammation. The clearest paradigms of this interconnection and overlap are caspase-family proteases, which can signal to cell death or the activation of proinflammatory cytokines, and NF-κB-family transcription factors, the ubiquitous rapid-response system centrally involved in the regulation of apoptosis and immune and inflammatory responses, in both vertebrates and invertebrates [1]. Given their central role in disease pathogenesis, the mechanisms underpinning these pathways are of paramount clinical significance. Notably, in many cancer types, the normally tight regulation of apoptosis and inflammation is frequently disrupted by an aberrant NF-κB activation [2]. While multiple control mechanisms normally ensure the prompt cessation of physiological NF-κB signalling, in most human cancers, numerous alterations constitutively activate NF-κB, enabling it to fuel tumour progression, metastatic dissemination and therapy resistance by regulating genes that suppress cancer-cell apoptosis and orchestrate inflammation in the tumour microenvironment (TME), thus hijacking the ancient connection between apoptotic and inflammatory pathways [2, 3]. Despite intense investigation, the mechanisms by which NF-κB mediates these functions in oncogenesis remain incompletely understood. Recently, we furthered their understanding in multiple myeloma, a cancer where plasma cells become addicted to NF-κB activation for survival. We showed that oncogenic NF-κB signalling mediates this effect by upregulating its pro-survival target gene, GADD45B, a member of the GADD45-gene family. Consequently, GADD45β is highly expressed in most multiple myelomas, where it suppresses apoptosis ensuing from spontaneous JNK/MAPK-pathway activation by inhibiting the JNK kinase, MKK7 [4].In addition to blocking cancer-cell apoptosis, oncogenic NF-κB signalling operates in the TME, thereby linking cancer to inflammation [3]. NF-κB activation in nonmalignant tumour-associated cells, especially those of the myeloid lineage, has been shown to enhance the production of cytokines and other specialised effectors that promote tumour-cell proliferation, tissue invasion and therapy resistance, while suppressing anti-tumour immune responses [5]. However, the notion that NF-κB would mediate its oncogenic functions in malignant cells and the TME via entirely different gene sets, which either suppress apoptosis or govern inflammation, is at odds with the overall architectural conservation and co-evolution of these processes. Recently, we demonstrated that this is indeed not the case [6]. We identified a dedicated axis of the NF-κB pathway, mediated by GADD45β, which integrates the NF-κB-dependent mechanism suppressing tumour-cell apopto-
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DOI：
10.1016/j.biocel.2017.12.020
发表时间：
2018-03
期刊：
The international journal of biochemistry & cell biology
影响因子：
--
作者：
Bennett J;Capece D;Begalli F;Verzella D;D'Andrea D;Tornatore L;Franzoso G
通讯作者：
Franzoso G
影响因子：
4.7
作者：
Begalli F;Bennett J;Capece D;Verzella D;D'Andrea D;Tornatore L;Franzoso G
通讯作者：
Franzoso G
影响因子：
50.3
作者：
Tornatore L;Sandomenico A;Raimondo D;Low C;Rocci A;Tralau-Stewart C;Capece D;D'Andrea D;Bua M;Boyle E;van Duin M;Zoppoli P;Jaxa-Chamiec A;Thotakura AK;Dyson J;Walker BA;Leonardi A;Chambery A;Driessen C;Sonneveld P;Morgan G;Palumbo A;Tramontano A;Rahemtulla A;Ruvo M;Franzoso G
通讯作者：
Franzoso G
影响因子：
14.9
作者：
Rozhdestvensky, TS;Tang, TH;Hüttenhofer, A
通讯作者：
Hüttenhofer, A
影响因子：
3.7
作者：
Sytnikova YA;Kubarenko AV;Schäfer A;Weber AN;Niehrs C
通讯作者：
Niehrs C