MAP3K20

更新于：2025-05-07

基本信息

别名

HCCS-4、Human cervical cancer suppressor gene 4 protein、Leucine zipper- and sterile alpha motif-containing kinase

+ [13]

简介

Stress-activated component of a protein kinase signal transduction cascade that promotes programmed cell death in response to various stress, such as ribosomal stress, osmotic shock and ionizing radiation (PubMed:10924358, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15350844, PubMed:15737997, PubMed:18331592, PubMed:20559024, PubMed:26999302, PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts by catalyzing phosphorylation of MAP kinase kinases, leading to activation of the JNK (MAPK8/JNK1, MAPK9/JNK2 and/or MAPK10/JNK3) and MAP kinase p38 (MAPK11, MAPK12, MAPK13 and/or MAPK14) pathways (PubMed:11042189, PubMed:11836244, PubMed:12220515, PubMed:14521931, PubMed:15172994, PubMed:15737997, PubMed:32289254, PubMed:32610081, PubMed:35857590). Activates JNK through phosphorylation of MAP2K4/MKK4 and MAP2K7/MKK7, and MAP kinase p38 gamma (MAPK12) via phosphorylation of MAP2K3/MKK3 and MAP2K6/MKK6 (PubMed:11836244, PubMed:12220515). Involved in stress associated with adrenergic stimulation: contributes to cardiac decompensation during periods of acute cardiac stress (PubMed:15350844, PubMed:21224381, PubMed:27859413). May be involved in regulation of S and G2 cell cycle checkpoint by mediating phosphorylation of CHEK2 (PubMed:15342622). Key component of the stress-activated protein kinase signaling cascade in response to ribotoxic stress or UV-B irradiation (PubMed:32289254, PubMed:32610081, PubMed:35857590). Acts as the proximal sensor of ribosome collisions during the ribotoxic stress response (RSR): directly binds to the ribosome by inserting its flexible C-terminus into the ribosomal intersubunit space, thereby acting as a sentinel for colliding ribosomes (PubMed:32289254, PubMed:32610081). Upon ribosome collisions, activates either the stress-activated protein kinase signal transduction cascade or the integrated stress response (ISR), leading to programmed cell death or cell survival, respectively (PubMed:32610081). Dangerous levels of ribosome collisions trigger the autophosphorylation and activation of MAP3K20, which dissociates from colliding ribosomes and phosphorylates MAP kinase kinases, leading to activation of the JNK and MAP kinase p38 pathways that promote programmed cell death (PubMed:32289254, PubMed:32610081). Less dangerous levels of ribosome collisions trigger the integrated stress response (ISR): MAP3K20 activates EIF2AK4/GCN2 independently of its protein-kinase activity, promoting EIF2AK4/GCN2-mediated phosphorylation of EIF2S1/eIF-2-alpha (PubMed:32610081). Also part of the stress-activated protein kinase signaling cascade triggering the NLRP1 inflammasome in response to UV-B irradiation: ribosome collisions activate MAP3K20, which directly phosphorylates NLRP1, leading to activation of the NLRP1 inflammasome and subsequent pyroptosis (PubMed:35857590). NLRP1 is also phosphorylated by MAP kinase p38 downstream of MAP3K20 (PubMed:35857590). Also acts as a histone kinase by phosphorylating histone H3 at 'Ser-28' (H3S28ph) (PubMed:15684425). Isoform that lacks the C-terminal region that mediates ribosome-binding: does not act as a sensor of ribosome collisions in response to ribotoxic stress (PubMed:32289254, PubMed:32610081, PubMed:35857590). May act as an antagonist of isoform ZAKalpha: interacts with isoform ZAKalpha, leading to decrease the expression of isoform ZAKalpha (PubMed:27859413).

关联

100 项与 MAP3K20 相关的临床结果

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100 项与 MAP3K20 相关的转化医学

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0 项与 MAP3K20 相关的专利（医药）

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134

项与 MAP3K20 相关的文献（医药）

2025-04-01·Clinical Genetics

Split Hand‐Foot Malformations—Unveiling Unique Molecular Diagnosis From a Brazilian Cohort

Article

作者: Bertola, Débora Romeo ; Krepischi, Ana Cristina Vitorino ; Bisneto, Edgard França ; Filho, Joao Bosco Oliveira ; Cás, Eduardo Da ; Ceroni, José Ricardo Magliocco ; Jorge, Alexander Augusto de Lima ; Yamamoto, Guilherme Lopes ; Castro, Matheus Augusto Araújo ; Kim, Chong Ae

ABSTRACTSplit hand‐foot malformation (SHFM) is a congenital limb malformation affecting primarily the central rays of the hands and/or feet, with variable expressivity, incomplete penetrance and syndromic forms. It is genetically heterogeneous, including point mutations and structural variants in different loci. Five individuals with SHFM were clinically evaluated in a Tertiary Center in Brazil: four of them presented additional, nonskeletal findings, including one individual with split foot, hand syndactyly, and ectodermal findings. Structural variants and point mutations in genes associated with SHFM were identified in all individuals. Our results highlight genetic heterogeneity observed in this group of skeletal disorders, alongside incomplete penetrance, a challenging task imposed on genetic counseling. Of note, an individual harboring a recurrent heterozygous variant in MAP3K20 presented a phenotype reminiscent of TP63‐related disorders, contrary to the one recently reported in the literature with prominent facial dysmorphisms, expanding the phenotypic spectrum of this newly recognized syndromic form of SHFM.

2024-12-01·Cancer biomarkers : section A of Disease markers

Pan-cancer genetic profiles of mitotic DNA integrity checkpoint protein kinases.

Article

作者: Liu, Hengrui ; Rasteh, Ayana Meegol ; Wang, Panpan

Background: The mitotic DNA integrity checkpoint signaling pathway is potentially involved in cancers that regulate genomic stability where protein kinases play a pivotal role. 16 total protein kinase genes are involved in this pathway: ATM, BRSK1, CDK1, CDK2, CHEK1, CHEK2, MAP3K20, NEK11, PLK1, PLK2, PLK3, PRKDC, STK33, TAOK1, TAOK2, and TAOK3. This study aims to provide pan-cancer profiles of the protein kinases in mitotic DNA integrity checkpoint signaling gene set for potential prognostic and diagnostic purposes, as well as future potential therapeutic targets for cancer in a clinical setting. Methods: Multi-omic data was acquired for the 16 genes; over 9000 samples of 33 types of cancer were analyzed to create pan-cancer profiles of SNV, CNV, methylation, mRNA expression, pathway crosstalk, and microRNA regulation networks. Results: The SNV profile showed that most of these genes have a high SNV mutation frequency across some cancer types, such as UCEC and SKCM. The CNVs of some of these genes are associated with the survival of UCEC, KIRP, and LGG. BRCA, KIRC, LUAD, and STAD might be affected by the mRNA expression of these genes which might involve regulation of copy number, methylation, and miRNA. In addition, these genes also cross-talk with some known cancer pathways. Conclusion: The protein kinases in mitotic DNA integrity checkpoint signaling may play a role in cancer development and, with adequate research, could potentially be developed as biomarkers for cancer diagnosis and prognosis. However, further efforts are necessary to validate their clinical value for diagnosis and prognosis and to develop practical applications in clinical settings. Nevertheless, these pan-cancer profiles offer a better overall understanding as well as useful information for future reference regarding mitotic DNA integrity checkpoint signaling in cancer.

2024-12-01·Molecular Cell

The ribotoxic stress response drives acute inflammation, cell death, and epidermal thickening in UV-irradiated skin in vivo

Article

作者: Koh, Li Fang ; Wu, Zhenzhen ; Martínez, José Francisco ; Firdaus, Muhammad Jasrie ; Zhong, Franklin L ; Toh, Gee Ann ; Snieckute, Goda ; Maartensson, Nina Loeth ; Andersen, Thomas Levin ; Jessen, Malin ; Haahr, Peter ; Blasius, Melanie ; Common, John E A ; Bekker-Jensen, Simon ; Vind, Anna Constance ; Gyrd-Hansen, Mads

Solar UVB light causes damage to the outermost layer of skin. This insult induces rapid local responses, such as dermal inflammation, keratinocyte cell death, and epidermal thickening, all of which have traditionally been associated with DNA damage response signaling. Another stress response that is activated by UVB light is the ribotoxic stress response (RSR), which depends on the ribosome-associated mitogen-activated protein 3 kinases (MAP3K) ZAKα and culminates in p38 and JNK activation. Using ZAK knockout mice, we here show that it is the RSR that is responsible for the early manifestation of UVB-induced skin inflammation and keratinocyte death and subsequent proliferation in vivo. We also show that the RSR controls both p38-mediated pyroptotic and JNK-mediated apoptotic programmed cell death of human keratinocytes in vitro. In sum, our work highlights that skin cells rely on a cytoplasmic and ribosomal stress signal rather than a nuclear and DNA-templated signal for rapid inflammatory responses to UV exposure.

项与 MAP3K20 相关的新闻（医药）

2025-02-21

·精准药物

石远凯/丁克教授：三代EGFR-TKI利厄替尼获批上市，创新结构设计带来更好透脑性

2025年1月14日，1类创新药利厄替尼成功获得国家药品监督管理局批准，用于既往经EGFR-TKI治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性非小细胞肺癌（NSCLC）成人患者的治疗。利厄替尼的上市，为国内患者带来了又一款自主研发的三代EGFR-TKI。【肿瘤资讯】特邀利厄替尼临床试验主要研究者、中国医学科学院肿瘤医院石远凯教授，主要开发者、中国科学院上海有机化学研究所丁克教授接受采访，分享利厄替尼上市的重要意义，及临床研究、研发阶段的宝贵经验。石远凯教授肿瘤学博士、肿瘤内科主任医师、博士研究生导师中国医学科学院北京协和医学院长聘教授中国医师协会肿瘤医师分会第一届、第二届会长中国抗癌协会肿瘤临床化疗专业委员会第三届、第四届主任委员中国抗癌协会淋巴瘤专业委员会第五届主任委员中国药学会抗肿瘤药物专业委员会第一届、第二届主任委员中国医疗保健国际交流促进会肿瘤内科分会第一届主任委员国家药监局药品审评专家咨询委员会委员上海证券交易所科技创新咨询委员会第一届、第二届委员中国癌症基金会第八届理事长雄安新区医学会第一届会长雄安新区癌症中心主任《癌症发生与治疗(英文)》/Cancer Pathogenesis and Therapy创刊主编抗肿瘤分子靶向药物临床研究北京市重点实验室主任丁克教授教授，研究员中国科学院上海有机化学研究所生命过程小分子调控全国重点实验室常务副主任暨南大学, 暨南大学药学院院长（2016-2021）The Innovation Medicine, Editorial Board Member Science Bulletin Life Science, Editorial Board Member China Science Life Science, Editorial Board Member iScience, Advisory Editorial Board Member J.Med.Chem, Associate Editor 中国药学会药物化学专业委员会, 副主委药物开发成果针对肿瘤临床耐药等重大需求，成功设计合成了：1）中国首个克服Bcr-AblT315I突变耐药的抗白血病新药奥雷巴替尼（耐立克®，2021年获批上市），被美国FDA和欧洲委员会授予“孤儿药”资格；2）克服非小细胞肺癌耐药的候选药物利厄替尼（奥壹新®，2025年获批上市）；3）高效的Axl抑制剂HH30134等其它5个候选新药处于中外临床4）世界首个选择性ZAK抑制剂、DDR1抑制剂、Akt3降解剂等类药性先导化合物。利厄替尼创新结构带来更好透脑性，为中国患者带来全新治疗选择石远凯教授：在中国的NSCLC患者中，EGFR突变是最常见的驱动基因，大约占肺腺癌患者的40%~50%，而在使用一代或二代EGFR-TKI治疗失败的患者中，约50%发生了EGFR T790M突变，需要使用可抑制EGFR T790M突变的三代EGFR-TKI。 EGFR突变的NSCLC患者容易发生脑转移，严重影响患者的预期生存时间和生活质量。在三代EGFR-TKI的开发过程中，颅内抗肿瘤活性是受到关注的重要因素。利厄替尼分子中引入萘胺基团，亲脂性更强，保障了药物有效透过血脑屏障；同时在萘胺基团的邻位引入氯原子取代，形成空间位阻，与萘胺基团直接形成稳定的构象，提高了对EGFR T790M的亲和力。临床前实验数据显示，利厄替尼针对EGFR L858R/T790M的酶活性IC50为0.3 nM，提示利厄替尼对于靶点的强结合力。利厄替尼的结构优势带来了更好的透脑性和抗肿瘤活性，为患者带来新的治疗选择。攻克脑转移是利厄替尼研发重要方向，独特萘胺结构增加透脑性丁克教授：如何解决脑转移，是我们在立项第一天就在思考的问题，为了克服脑转移，我们需要在分子设计中使其可以有效透过血脑屏障：首先，血脑屏障的形成主要依靠多重亲脂性膜结构，因此分子需要具有足够的亲脂性才能透过血脑屏障，因此我们在分子结构中引进了萘胺基团。此外，还需要将分子尽可能变小、去除阴离子形成条件等。结合知识积累与研发经验，最终我们进行了结构上的调整，使得分子可以更好透过血脑屏障，起到治疗颅内病灶的效果。利厄替尼IIb期临床研究数据解读，80mg bid给药患者有望获益更多石远凯教授：此前，我们开展了利厄替尼二线治疗EGFR T790M突变的局部晚期或转移性NSCLC的IIb期临床研究。研究纳入了既往一代或二代EGFR-TKI耐药后EGFR T790M突变的局部晚期或转移性NSCLC患者，允许原发性EGFR T790M患者入组。患者接受利厄替尼治疗直至疾病进展或出现不可耐受的毒副反应。研究主要终点是由IRC基于RECIST V1.1评估的客观缓解率（ORR），次要终点则包括疾病控制率（DCR）、缓解持续时间（DoR）、无进展生存期（PFS）、总生存期（OS）及安全性等。研究总计入组了301例患者，其中包括2例原发EGFR T790M突变的患者。入组患者的基线状况与真实世界情况相当，基线时存在中枢神经系统（CNS）转移的患者占比为32.9%。结果显示，利厄替尼治疗一代或二代EGFR-TKI耐药并且存在EGFR T790M突变患者，ORR为68.8%，DCR为92.4%，mDoR为11.1个月，mPFS为11.0个月，12个月PFS率达为47.1%，mOS为28.1个月。值得关注的是，利厄替尼剂量调整到80mg BID的患者取得了更好的疗效，这部分患者的ORR为76.8%，mPFS为13.7个月，mOS为42.5个月。此外，不同基线状态的患者获益一致，无论基线是否存在CNS转移均可获益。在99例基线CNS转移患者中，ORR为64.6%，mPFS为9.7个月。在41例CNS病灶可评估的患者中，IRC评估的最佳颅内ORR为65.9%，颅内DCR为100%，mCNS-DoR为11.1个月，mCNS-PFS为10.6个月。安全性方面，总体安全性可控，患者可耐受。总体看来，利厄替尼为既往经过一代或二代EGFR-TKI治疗后出现EGFR T790M突变的患者带来了明显的肿瘤缓解和生存获益，特别是通过剂量调整策略，有望进一步提高疗效，80mg BID剂量给患者带来的mPFS和mOS分别为13.7个月和42.5个月。基线脑转移患者也可以有很好的疗效，有效控制了CNS病灶的进展。利厄替尼安全可控，耐受性良好。利厄替尼积极拓展一线治疗应用，帮助更多患者享受精准治疗获益石远凯教授：2025年1月14日，利厄替尼获得国家药品监督管理局的批准上市，用于既往经EGFR-TKI治疗时或治疗后出现疾病进展，并且经检测确认存在EGFR T790M突变阳性的局部晚期或转移性NSCLC成人患者的治疗。利厄替尼的上市，为临床医生提供了一个对抗EGFR阳性NSCLC的“有力武器”。对于经一代或二代EGFR-TKI治疗后广泛进展的NSCLC患者，如果经基因检测诊断为EGFR T790M突变，则可以选择利厄替尼作为二线治疗药物，以继续使患者从精准靶向治疗中获益。目前，我们已经开展了利厄替尼一线治疗EGFR 19del/21L858R突变的晚期NSCLC患者的临床研究。2024年8月，利厄替尼一线治疗适应症的上市申请获得国家药品监督管理局受理，目前正在审评中，或将有望在不久后正式获批上市。未来，利厄替尼将在EGFR突变晚期NSCLC的临床实践中得到越来越多的应用，帮助更多患者享受精准靶向治疗带来的获益。回顾研发历程，以临床需求为出发点，利厄替尼历经15年成功上市丁克教授：祝贺利厄替尼成功上市，该项目自2009年立项以来，近15年的研发过程感慨颇多。利厄替尼的立项从临床需求出发，直至成功获批，回顾研发经历，我们非常感谢参与其中的每位合作人员。在NSCLC的治疗中，吉非替尼、厄洛替尼等一代EGFR-TKI的出现，开辟了肿瘤精准治疗的新时代，随着药物的使用，耐药问题难以避免。进一步研究发现，很大一部分患者耐药是由于出现了T790M突变，T790M突变导致了EGFR-TKI与靶标的内源性配体ATP竞争能力的下降，基于此，研究者尝试利用EGFR的ATP结合口袋边缘C797位点研发共价抑制剂，通过与其形成共价键来与EGFR结合，形成不可逆的EGFR抑制剂，从而提高与ATP的竞争能力，解决耐药，自此诞生了第三代EGFR-TKI。然而，尽管具备化学理论基础，三代EGFR-TKI的研发却并不顺利。人体内存在空间结构与T790M突变型类似的EGFR野生型，难以实现选择性抑制。直至2009年哈佛大学发表于Nature的文章报道，发现了选择性抑制T790M突变的WZ4002分子，基于此，三代EGFR-TKI的研发开启了全新篇章。我们团队结合Nature报道的分子结构特征与中国临床实际需求，通过与临床医生的充分交流，立项了利厄替尼项目。基于对EGFR T790M蛋白结构特征的理解，团队前后合成了6类不同化学结构总计超1000种分子，投入了6~7名博士生的工作，报道了多个可以选择性抑制EGFR T790M的分子，最终诞生了利厄替尼（ASK120067）。后续奥赛康团队推进了利厄替尼的临床研究进程，在临床专家的共同努力下，最终得以获批上市。结构优势达成更稳定构象，利厄替尼可更好结合T790M突变丁克教授：我们在设计利厄替尼时，三代EGFR-TKI奥希替尼尚未问世。后期北京大学云彩红教授团队发表于Journal of Medicinal Chemistry的研究成果发现，奥希替尼在与EGFR T790M结合时，其吲哚基团会发生翻转，使构象产生变化，翻转至特定位置时，才能与EGFR T790M的甲硫氨酸发生作用，达到选择性抑制的作用。因此，奥希替尼分子需要在生理条件下产生特定的动态构象调整才能发挥作用。而我们在设计利厄替尼时，有意引入了萘胺基团，并在萘胺基团的邻位引入氯原子取代，达到更稳定的构象，使其更好地与EGFR T790M突变相互结合，减少能量消耗，提高了生物学活性。因此，在设计中我们并不是为了解决奥希替尼的问题，但后期针对奥希替尼的结构分析结果，的确为利厄替尼获得更优的试验结果作出了科学的解释。声明：发表/转载本文仅仅是出于传播信息的需要，并不意味着代表本公众号观点或证实其内容的真实性。据此内容作出的任何判断，后果自负。若有侵权，告知必删！长按关注本公众号粉丝群/投稿/授权/广告等请联系公众号助手觉得本文好看，请点这里↓

孤儿药上市批准申请上市快速通道

2024-07-17

·生物探索

Cell | 核糖毒性应激反应驱动紫外线介导的细胞程序性死亡

引言紫外线（UV）辐射会诱导DNA损伤并激活DNA损伤反应（DDR）途径，从而阻滞细胞周期为DNA修复留出时间，当DNA损伤严重到难以修复时就会激活细胞凋亡【1-3】。UV辐射诱导DNA损伤的研究早已被人们熟知，但是关于UV也可以诱导RNA损伤的产生却较少被提及。有研究发现，UV可以通过光化学反应生成嘧啶二聚体和其他光产物，这些产物可以诱导转录组范围内的RNA损伤，同时UV损伤还会导致翻译缺陷，核糖体会停滞在富含嘧啶的受损密码子上，引起核糖体碰撞，从而激活核糖毒性应激反应（ribotoxic stress response, RSR）【4-5】。RSR将会激活下游的ZAK和GCN2激酶，ZAK激酶激活MAPK途径介导细胞周期停滞和细胞凋亡，GCN2激酶的激活导致eIF2α磷酸化和通过整合应激反应（ISR）介导的蛋白合成抑制【6-10】。虽然已经发现UV诱导的RNA损伤可以通过核糖体碰撞激活RSR和ISR通路，但是这些研究未能解决一个关键问题：细胞如何整合这些反应来决定细胞的命运。 7月11日，来自美国约翰霍普金斯大学医学院的Rachel Green课题组在Cell上发表了研究论文The ribotoxic stress response drives UV-mediated cell death。在本研究中，作者通过全面的分析揭示了UV照射后细胞内发生的各种核酸损伤应激反应作用，发现RSR在UV依赖的程序性细胞死亡中比DDR起到更为关键的作用。这一发现突破了传统的认知，为理解细胞如何应对UV损伤提供了新的见解。为了阐明这个问题，作者首先研究了细胞对UV强度做出的分级反应，在较低强度UV辐射时细胞主要停滞在G2期，死亡细胞极少；而较高UV强度则导致凋亡细胞比例显著增加。在低剂量UV照射后数分钟内可以观察到核糖体碰撞的积累，并在几个小时内被清除。对低剂量UV照射后RSR、ISR和DDR三种信号通路的激活动力学进行分析发现：（1）代表RSR途径的ZAK激酶几分钟内就被磷酸化并在15分钟时达到峰值，与此同时ZAK下游的p38和JNK快速被激活，表明RSR途径在早期响应中高度协同；（2）ISR途径中的eIF2α在UV照射后早期被磷酸化并不断增加，说明ISR信号通路在应对UV照射后逐渐增强；（3）DDR的效应分子磷酸化速度较慢，显示出与RSR和ISR不同的激活模式。作者还通过磷酸化和蛋白质组学分析也进一步证实了这一发现，即UV照射不同应激反应的顺序激活模式，并强调了核糖体介导的信号转导在最早期的主导地位。接下来，作者分别详细的研究了ZAK和GCN2在UV处理后对磷酸化蛋白质组变化的作用。通过敲除ZAK或GCN2，以及使用两种激酶的特异性抑制剂处理，作者研究发现ZAK在早期响应中起着关键作用，而GCN2在p38效应激酶的调控中发挥重要作用。此外，RSR和DDR信号通路在UV响应过程中是独立运行的，因为使用DDR效应激酶ATR的抑制剂处理可以发现DDR特异性磷酸化位点与ZAK激酶依赖的磷酸化位点没有相关性。对ZAK和ATR在决定细胞命运中的作用进行分析后，作者发现ZAK主要驱动UV响应的早期凋亡和G2/M检测点激活，而ATR在细胞增殖和DNA修复中起到了关键作用。相对应的是，GCN2通过磷酸化eIF2α和抑制mTOR活性来阻止翻译起始，从而限制受损mRNA上核糖体碰撞的积累；缺乏GCN2的细胞表现出更高的核糖体碰撞和RSR（ZAK）的过度激活，导致JNK信号通路的持续高活性和更高的细胞凋亡率；并且ZAK和GCN2在调控细胞应对UV损伤中的作用独立且互不影响。在确定核糖体碰撞是如何激活RSR之后，作者将目光聚焦到RSR信号转导的衰减上。对此，作者分析了ZAK在响应RSR时的激活和降解机制。研究发现，ZAK的激活涉及多种磷酸化位点的动态变化，而降解主要通过CRL1 E3泛素连接酶复合物介导，ZAK的自磷酸化位点在降解时发挥了重要作用。并且ZAK的多结构域使其能够在响应核糖体碰撞时发挥复杂的调控功能。最后，作者探究了RSR信号转导的衰减是如何影响细胞命运的决定。通过一些列实验和分析，作者发现ZAK降解通过负反馈调控JNK信号，减少细胞凋亡，并使细胞对持续的核糖毒性应激产生耐受性。模式图（Credit: Cell）总的来说，这篇文章系统的研究了UV辐射诱导核酸损伤后的多种应激反应激活模式，揭示了各个途径在细胞命运决定的重要作用，特别是在细胞经历核糖体碰撞和核糖毒性应激时的细胞命运是如何被驱动的。深入研究了ZAK的激活和降解机制，有助于以此为靶标开发新药物来调节细胞应激反应，这对于治疗与应激响应失调相关的疾病具有重要潜力。参考文献 1. Mare ́ chal, A., and Zou, L. (2013). DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb. Perspect. Biol. 5, a012716. 2. Zhou, B.B., and Elledge, S.J. (2000). The DNA damage response: putting checkpoints in perspective. Nature 408, 433–439. 3. Saldivar, J.C., Cortez, D., and Cimprich, K.A. (2017). The essential kinase ATR: ensuring faithful duplication of a challenging genome. Nat. Rev. Mol. Cell Biol. 18, 622–636. 4. Wurtmann, E.J., and Wolin, S.L. (2009). RNA under attack: Cellular handling of RNA damage. Crit. Rev. Biochem. Mol. Biol. 44, 34–49. 5. Wu, C.C.-C., Peterson, A., Zinshteyn, B., Regot, S., and Green, R. (2020). Ribosome Collisions Trigger General Stress Responses to Regulate Cell Fate. Cell 182, 404–416.e14. 6. Jandhyala, D.M., Ahluwalia, A., Obrig, T., and Thorpe, C.M. (2008). ZAK: a MAP3Kinase that transduces Shiga toxin- and ricin-induced proinflammatory cytokine expression. Cell Microbiol. 10, 1468–1477. 7. Sauter, K.A.D., Magun, E.A., Iordanov, M.S., and Magun, B.E. (2010). ZAK is required for doxorubicin, a novel ribotoxic stressor, to induce SAPK activation and apoptosis in HaCaT cells. Cancer Biol. Ther. 10, 258–266. 8. Wang, X., Mader, M.M., Toth, J.E., Yu, X., Jin, N., Campbell, R.M., Smallwood, J.K., Christe, M.E., Chatterjee, A., Goodson, T., et al. (2005). Complete Inhibition of Anisomycin and UV Radiation but Not Cytokine Induced JNK and p38 Activation by an Aryl-substituted Dihydropyrrolopyrazole Quinoline and Mixed Lineage Kinase 7 Small Interfering RNA. J. Biol. Chem. 280, 19298–19305. 9. Stoneley, M., Harvey, R.F., Mulroney, T.E., Mordue, R., Jukes-Jones, R., Cain, K., Lilley, K.S., Sawarkar, R., and Willis, A.E. (2022). Unresolved stalled ribosome complexes restrict cell-cycle progression after genotoxic stress. Mol. Cell 82, 1557–1572.e7. 10. Vind, A.C., Snieckute, G., Blasius, M., Tiedje, C., Krogh, N., Bekker-Jensen, D.B., Andersen, K.L., Nordgaard, C., Tollenaere, M.A.X., Lund, A.H., et al. (2020). ZAKa Recognizes Stalled Ribosomes through Partially Redundant Sensor Domains. Mol. Cell 78, 700–713.e7. https://doi.org/10.1016/j.cell.2024.05.018 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-07-02

·Science Daily

UV radiation damage leads to ribosome roadblocks, causing early skin cell death

In a recent study, researchers suggest the cell's messenger RNA (mRNA) -- the major translator and regulator of genetic material -- along with a critical protein called ZAK, spur the cell's initial response to UV radiation damage and play a critical role in whether the cell lives or dies. In a recent study, researchers at Johns Hopkins Medicine suggest the cell's messenger RNA (mRNA) -- the major translator and regulator of genetic material -- along with a critical protein called ZAK, spur the cell's initial response to UV radiation damage and play a critical role in whether the cell lives or dies. While UV radiation has long been known to damage DNA, it also damages mRNA, and the latest findings, published June 5 in Cell, indicate that mRNAs act as first responders in telling the cells how to manage the stress. "RNA is a canary in the coal mine. It's telling the cell, 'We've got major damage here and we need to do something,'" says Rachel Green, Ph.D., a Bloomberg Distinguished Professor of Molecular Biology and Genetics and Daniel Nathans Director of the Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine. Green, also an investigator at Howard Hughes Medical Institute, is the corresponding author of the new study. ZAK is a key player in a process that identifies cellular damage by sensing the collisions of ribosomes, tiny macromolecular machines that help RNA translate the language of genes into the language of proteins. Collisions occur when ribosomes move along UV-damaged mRNAs and, unable to decode the damaged message, cause stalled ribosomes to get "rear-ended" by upstream ribosomes. Ribosome collisions activate ZAK, which triggers a cellular signaling program known as the ribotoxic stress response. ZAK then instigates a cascade of downstream events that decide the cell's fate. A more comprehensive understanding of how cellular life-and-death decisions are made upon encountering UV radiation could help investigators understand underlying causes of skin and other cancers, says Niladri Sinha, Ph.D., Jane Coffin Childs Memorial Fund Postdoctoral Fellow at Johns Hopkins School of Medicine. Companies developing drugs that target ribosomes may also find that ZAK could be a driver of cell death across cancer types, he says. The findings indicate that ZAK senses the extent of cellular damage and responds depending on how much UV radiation the cell receives, offering a more nuanced understanding of UV-caused cell death and identifying new ways to keep ZAK's activity under control, Green says. "There are graded ways that ZAK responds, it's not all or nothing," she says. The research also "very clearly shows" that, for example, a skin cell's fate in the immediate aftermath of UV radiation is "driven primarily by the extent of colliding ribosomes and ZAK signaling," Green says. "In this regime, DNA damage and the well-characterized DNA damage response pathway, including the key protein p53, do not significantly determine cell fate decisions," she says. DNA damage repair is critical and occurs in a subset of cells that are copying their genetic material, but these pathways are not the major "deciders" of cell fate, she says. Green co-led the research with Sergi Regot, Ph.D., associate professor of molecular biology and genetics at the Johns Hopkins University School of Medicine, and Alban Ordureau, Ph.D., assistant member of the Cell Biology Program at Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute and an assistant professor at Weill Cornell. To conduct their research, the scientists exposed human cellular models to a UV lamp mimicking the sun's radiation. Using proteomics to understand cell signaling in an approach led by Ordureau, they evaluated ZAK's role and made predictions about how cells would respond to different levels of stress. From there, live cell imaging experiments led by Regot, in addition to in-house ribosome biochemistry -- the workhorse of Green's laboratory -- helped characterize how cellular death is regulated as a consequence of ZAK-mediated UV radiation. In the future, the researchers plan to investigate cell types with different protein synthesis regimes, including those in melanoma and other cancers. The researchers suspect that fast-growing cells will rely on ZAK-mediated regulation more than others, Green says. Funding for this research was provided by the Howard Hughes Medical Institute, the National Institutes of Health (NIH 1R35GM133499), a National Science Foundation Career grant, the Jane Coffin Childs Memorial Fund for Medical Research Fellowship, and the National Institute of General Medical Sciences, Sloan Kettering Institute startup funds, Pew Charitable Trusts, a Memorial Sloan Kettering Cancer Center support grant, and the Basic Science Research Program from the National Research Foundation of Korea; Ministry of Education. Other scientists who contributed to this study are Connor McKenney, Zhong Y. Yeow, and Jeffrey J. Li of Johns Hopkins; Ki Hong Nam of Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute; and Tomer M. Yaron-Barir, Jared L. Johnson, Emily M. Huntsman and Lewis C. Cantley of Weill Cornell Medicine. Green is a member of the scientific advisory board of Alltrna, Initial Therapeutics and Arrakis Pharmaceuticals, consults for Vertex Pharmaceuticals, Bristol-Myers Squibb (Celgene), Monta Rosa Therapeutics and Flagship Pioneering, and served on the scientific advisory board at Moderna.

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