更新于：2024-11-01

PPP1R15A

更新于：2024-11-01

基本信息

别名

GADD34、Growth arrest and DNA damage-inducible protein GADD34、growth arrest and DNA-damage-inducible 34

+ [5]

简介

Recruits the serine/threonine-protein phosphatase PPP1CA to prevents excessive phosphorylation of the translation initiation factor eIF-2A/EIF2S1, thereby reversing the shut-off of protein synthesis initiated by stress-inducible kinases and facilitating recovery of cells from stress (PubMed:26742780, PubMed:26095357). Down-regulates the TGF-beta signaling pathway by promoting dephosphorylation of TGFB1 by PP1 (PubMed:14718519). May promote apoptosis by inducing p53/TP53 phosphorylation on 'Ser-15' (PubMed:14635196). Plays an essential role in autophagy by tuning translation during starvation, thus enabling lysosomal biogenesis and a sustained autophagic flux (PubMed:32978159). Acts also a viral restriction factor by attenuating HIV-1 replication (PubMed:31778897). Mechanistically, mediates the inhibition of HIV-1 TAR RNA-mediated translation (PubMed:31778897). (Microbial infection) Promotes enterovirus 71 replication by mediating the internal ribosome entry site (IRES) activity of viral 5'-UTR.

关联

项与 PPP1R15A 相关的药物

Icerguastat

靶点

PPP1R15A

作用机制

PPP1R15A抑制剂

在研机构

Inflectis Bioscience SAS [+1]

原研机构

The Medical Research Council

在研适应症

肌萎缩侧索硬化 [+1]

非在研适应症

多发性硬化症

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

IFB-048

靶点

PPP1R15A

作用机制

PPP1R15A抑制剂

在研机构-

原研机构

Inflectis Bioscience SAS

在研适应症-

非在研适应症

多发性硬化症

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

GL-GP inhibitors(Boehringer Ingelheim)

靶点

PPP1R15A x PYG

作用机制

PPP1R15A抑制剂 [+1]

在研机构-

原研机构

Boehringer Ingelheim Pharma GmbH & Co., KG

在研适应症-

非在研适应症

2型糖尿病

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

项与 PPP1R15A 相关的临床试验

NCT05508074 / Active, not recruiting临床2期

A Double-blind, Placebo-controlled, Exploratory Randomised Clinical Trial to Assess the Safety and Efficacy of IFB-088 Plus Riluzole 100 mg vs Placebo Plus Riluzole 100 mg in Patients With Bulbar-onset Amyotrophic Lateral Sclerosis.

Prospective, international, randomised, double-blind, placebo controlled, multicentre, parallel group study. Patients will be randomised in a 2:1 allocation ratio to receive either IFB-088 + riluzole 100 mg or placebo + riluzole 100 mg. This clinical trial is an exploratory study, designed to show a signal of efficacy of IFB-088 through ALSFRS-R, MITOS and King's College. Respiratory function will be followed through SVC. Biomarkers and quality of life will also be evaluated throughout the study.
Patients will be treated over a 6-month period. After a screening/consent visit, patients will undergo clinic visits at randomisation (V0), at 2 weeks (V1), and at months 1 (V2), 3 (V3) and 6 (V4). One week after V0, the patient will undergo urine analysis (dipstick)and blood sampling for measurement of creatinine
, as well as blood sampling for measurement of creatinine and calculation of eGFR at months 2, 4 and 5. At the V2 visit, in addition to other assessments, patients will undergo blood sampling for PK measurements and urine sampling for crystalluria examination. Blood and urine chemistry, as well as physical examination and vital signs assessment to assess safety will be performed at each visit for safety purpose and crystalluria examination will be repeated at the follow-up visit, performed one month ± one week after V4.

开始日期2022-12-02

申办/合作机构

Inflectis Bioscience SAS

EUCTR2021-003875-32-IT / Unknown status临床2期

A double-blind, placebo-controlled, exploratory randomised clinical trial to assess the safety and efficacy of IFB-088 plus riluzole 100 mg vs placebo plus riluzole 100 mg in patients with bulbar-onset amyotrophic lateral sclerosis (Study TRIALS) - TRIALS

开始日期2022-02-15

申办/合作机构

Inflectis Bioscience SAS

NCT03610334 / Completed临床1期

A Double-blind, Randomized, Placebo-controlled, Combined Single and Multiple Ascending Dose Study to Investigate the Safety, Tolerability and Pharmacokinetic Profile of IFB-088, in Healthy Volunteers

This is the first study of single and multiple doses of IFB-088 in human subjects. The current study is designed to assess in the first part, the safety, tolerability, plasma and urine pharmacokinetics (PK) of single oral doses of IFB-088 in healthy subjects (Single Ascending Doses - SAD) and in a second part safety, tolerability, plasma and urine pharmacokinetics (PK) of multiple oral doses of IFB-088 in healthy subjects (Multiple Ascending Doses - MAD)

开始日期2018-06-21

申办/合作机构

Inflectis Bioscience SAS

[+4]

100 项与 PPP1R15A 相关的临床结果

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100 项与 PPP1R15A 相关的转化医学

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0 项与 PPP1R15A 相关的专利（医药）

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578

项与 PPP1R15A 相关的文献（医药）

2024-12-01·Applied Microbiology and Biotechnology

Enhanced ER protein processing gene expression increases rAAV yield and full capsid ratio in HEK293 cells

Article

作者: Yoon, Seongkyu ; McNally, David ; Fu, Qiang ; Wang, Yongdan ; Xie, Dongming ; Qin, Jiansong

The recombinant adeno-associated virus (rAAV) vector is among the most promising viral vectors in gene therapy. However, the limited manufacturing capacity in human embryonic kidney (HEK) cells is a barrier to rAAV commercialization. We investigated the impact of endoplasmic reticulum (ER) protein processing and apoptotic genes on transient rAAV production in HEK293 cells. We selected four candidate genes based on prior transcriptomic studies: XBP1, GADD34 / PPP1R15A, HSPA6, and BCL2. These genes were stably integrated into HEK293 host cells. Traditional triple-plasmid transient transfection was used to assess the vector production capability and the quality of both the overexpressed stable pools and the parental cells. We show that the overexpression of XBP1, HSPA6, and GADD34 increases rAAV productivity by up to 100% and increases specific rAAV productivity by up to 78% in HEK293T cells. Additionally, more prominent improvement associated with ER protein processing gene overexpression was observed when parental cell productivity was high, but no substantial variation was detected under low-producing conditions. We also confirmed genome titer improvement across different serotypes (AAV2 and AAV8) and different cell lines (HEK293T and HEK293); however, the extent of improvement may vary. This study unveiled the importance of ER protein processing pathways in viral particle synthesis, capsid assembly, and vector production. KEY POINTS: • Upregulation of endoplasmic reticulum (ER) protein processing (XBP1, HSPA6, and GADD34) leads to a maximum 100% increase in rAAV productivity and a maximum 78% boost in specific rAAV productivity in HEK293T cells • The enhancement in productivity can be validated across different HEK293 cell lines and can be used for the production of various AAV serotypes, although the extent of the enhancement might vary slightly • The more pronounced improvements linked to overexpressing ER protein processing genes were observed when parental cell productivity was high, with minimal variation noted under low-producing conditions.

2024-09-03·Proceedings of the National Academy of Sciences

Alternating binding and p97-mediated dissociation of SDS22 and I3 recycles active PP1 between holophosphatases

Article

作者: Kueck, Anja F. ; Meyer, Hemmo ; van den Boom, Johannes ; Ron, David ; Koska, Sandra

Protein phosphatase-1 catalytic subunit (PP1) joins diverse targeting subunits to form holophosphatases that regulate many cellular processes. Newly synthesized PP1 is known to be transiently sequestered in an inhibitory complex with Suppressor-of-Dis2-number-2 (SDS22) and Inhibitor-3 (I3), which is disassembled by the ATPases Associated with diverse cellular Activities plus (AAA+) protein p97. Here, we show that the SDS22-PP1-I3 complex also acts as a thermodynamic sink for mature PP1 and that cycles of SDS22-PP1-I3 formation and p97-driven disassembly regulate PP1 function and subunit exchange beyond PP1 biogenesis. Förster Resonance energy transfer (FRET) analysis of labeled proteins in vitro revealed that in the p97-mediated disassembly step, both SDS22 and I3 dissociate concomitantly, releasing PP1. In presence of a targeting subunit, for instance Growth Arrest and DNA Damage-inducible protein 34 (GADD34), liberated PP1 formed an active holophosphatase that dephosphorylated its substrate, eukaryotic translation initiation factor 2 alpha (eIF2α). Inhibition of p97 results in displacement of the GADD34 targeting subunit by rebinding of PP1 to SDS22 and I3 indicating that the SDS22-PP1-I3 complex is thermodynamically favored. Likewise, p97 inhibition in cells causes rapid sequestration of PP1 by free SDS22 and I3 at the expense of other subunits. This suggests that PP1 exists in a steady state maintained by spontaneous SDS22-PP1-I3 formation and adenosine triphosphate (ATP) hydrolysis, p97-driven disassembly that recycles active PP1 between different holophosphatase complexes to warrant a dynamic holophosphatase landscape.

2024-08-01·Molecular Neurobiology

Downregulation of ATF-4 Attenuates the Endoplasmic Reticulum Stress–Mediated Neuroinflammation and Cognitive Impairment in Experimentally Induced Alzheimer’s Disease Model

Article

作者: Jindal, Garima ; Suramya, Suramya ; Mangla, Anuradha ; Akhter, Juheb ; Goswami, Poonam ; Ahmad, Shahzad ; Raisuddin, Sheikh

Protein aggregation is invariably associated with the inflammation as a factor in Alzheimer's disease (AD). We investigated the interaction between downstream factors of endoplasmic reticulum (ER) stress pathway and inflammation, with implications in cognitive impairment in AD. Amyloid-β (Aβ)_(1-42) was administered by bilateral intracerebroventricular (icv) injection in the brain of adult male Wistar rats to experimentally develop AD. The cognitive impairment was assessed by measuring behavioral parameters such as Morris water maze and novel object recognition tests. Levels of pro-inflammatory cytokines such as interleukin (IL)-1β and tumor necrosis factor (TNF)-α and anti-inflammatory cytokines IL-4 and IL-10 were measured by the enzyme-linked immunosorbent assay (ELISA) in different rat brain regions. Inflammatory marker proteins such as cyclo-oxygenase (COX)-2 and phosphorylation of nuclear factor kappa B (NF-КB) (p65) were measured by the western blotting. Gene expression of ER stress downstream factors such as ATF-4, CHOP, and GADD-34 was analyzed by qRT-PCR. Histological studies were performed to check Aβ accumulation and neuronal degeneration. Integrated stress response inhibitor (ISRIB) was used to confirm the specific role of ER stress-mediated inflammation in cognitive impairment. Administration of Aβ_(1-42) resulted in alteration in levels of inflammatory cytokines, inflammatory proteins, and mRNA levels of ER stress downstream factors. ISRIB treatment resulted in attenuation of Aβ_(1-42)-induced ER stress, inflammation, neurodegeneration, and cognitive impairment in rats. These results indicate that ER stress-mediated inflammation potentiates the cognitive impairment in AD. An understanding of cascade of events, interaction of ER stress which was a hallmark of the present investigation together with inflammation and modulation of downstream signalling factors could serve as potent biomarkers to study AD progression.

项与 PPP1R15A 相关的新闻（医药）

2024-10-29

·PRNewswire

Discovery of cancer risk associations for six novel genes

REYKJAVIK, Iceland, Oct. 29, 2024 /PRNewswire/ --Scientists at deCODE genetics/Amgen, and their collaborators have discovered six novel genes with rare germline variants that associate with cancer risk. The findings are published today in Nature Genetics under the title "Gene-based burden tests of rare germline variants identify six cancer susceptibility genes". Continue Reading Kari Stefansson senior author of the paper, “Gene-based burden tests of rare germline variants identify six cancer susceptibility genes”, published today in Nature Genetics, discusses the paper with Erna V. Ivarsdottir first author on the paper. Kari Stefansson CEO of deCODE genetics and senior author on the paper in Nature Genetics, with Erna V. Ivarsdottir scientists at deCODE genetics and first author. A subset of cancers arises in individuals who are born with rare sequence variants that significantly alter their cancer risk. The discovery of such variants, like those in the BRCA1- and BRCA2 genes, has led to improved early cancer detection and the development of targeted therapies, ultimately reducing the cancer burden and improving prognosis of those carrying these mutations. In this study, the scientists analysed three large genetic datasets from individuals of European descent, including 130,991 cancer patients and 733,486 controls. Through a gene-based burden association analysis across 22 different cancer types, they found four novel genes associated with a risk of developing cancer; the pro-apoptotic BIK for prostate cancer, the autophagy involved ATG12 for colorectal cancer, TG for thyroid cancer, and CMTR2 for both lung cancer and cutaneous melanoma. The relative increase in cancer risk conferred by these variants was substantial (90-295%), but it should be noted that the design of the study does not allow accurate assessment of absolute lifetime cancer risk. Additionally, the researchers found the first genes with rare variants that are associated with a decreased risk of cancer. Specifically, loss of AURKB was found to protect against any cancer type, and loss of PPP1R15A was associated with 53% lower risk of breast cancer. This suggests that inhibition of PPP1R15A may be a therapeutic option for breast cancer. The study revealed new insight into the biological mechanisms involved in cancer predisposition that will hopefully lead to better screening and treatment strategies. Video - Photo - SOURCE deCODE genetics WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

2023-03-15

·生物谷

Nat Cell Biol | 陈水冰团队利用类器官揭示CIART/NR4A1/RXR信号通路在调控新冠病毒感染中的重要作用

截至目前，新冠病毒大流行在全球范围造成了超过七亿六千万感染病例，其中死亡病例超过六百八十万。新冠病毒不仅感染呼吸系统，还可以感染人体多种其他组织，包括肝脏，胰腺，肾脏，大脑，肠道，心脏等等。近年来，人多能干细胞来源的类器官作为一种新兴的模型系统被广泛用于研究疾病发生和组织器官发育。在之前的研究中，类器官被用于研究新冠病毒的易感性，病毒与宿主细胞相互作用，以及药物筛选等。然而，调控新冠病毒感染的机理并没有完全阐明，能不能通过在不同组织中靶向共同的因子抑制新冠病毒感染也不清楚。2023年3月15日，康奈尔大学威尔医学院陈水冰团队在Nature Cell Biology发表了题为 A Multi-Organoid Platform Identifies CIART as a Key Factor for SARS-CoV-2 Infection 的研究论文。研究人员利用人多能干细胞分化得到了可以被新冠病毒高效感染的心肌细胞，肺泡类器官，气管类器官。在此基础上，研究人员用不同剂量的新冠病毒感染了这些细胞/类器官，并通过RNA-seq系统分析了新冠病毒感染引起的转录组变化。过往的研究表明，新冠病毒可以通过上调某些宿主基因，比如ACE2的表达而进一步促进感染。本研究鉴定了18个在不同细胞/类器官中被新冠病毒感染后上调的宿主基因，进一步在心肌细胞中逐一敲除这些基因证实CIART，EGR1，FOS，H2AC6，H2BC5，JUN，MXD1，NR1D1，NR4A1，NR4A3，PPP1R15A，SOCS3，TIPARP影响新冠病毒感染，其中敲除CIART抑制感染效果最显著。研究人员进一步利用CRISPR/Cas9基因编辑在人多能干细胞中敲除CIART，并分化得到野生型和CIART敲除心肌细胞，肺泡类器官，气管类器官。与野生型对照相比，CIART敲除细胞/类器官抵抗新冠病毒感染能力显著增强。scRNA-seq显示气管类器官中的多种细胞类型，尤其是纤毛样细胞在CIART敲除后对新冠病毒更不易感。研究发现，不止新冠病毒，流感病毒感染同样可以上调CIART表达水平，提示CIART可能与多种病毒感染有关。之前的研究显示CIART基因编码调控昼夜节律的转录因子，研究人员进一步通过CUT&RUN在心肌细胞全基因组范围寻找受CIART调控的下游因子，结合CIART敲除和野生型心肌细胞的RNA-seq，ATAC-seq数据，研究人员发现CIART可以结合在NR4A1的启动子区域，影响NR4A1基因序列的染色质可及性。在心肌细胞中敲除CIART，可以下调NR4A1表达水平。这些结果表明NR4A1是受CIART调控的下游因子。有意思的是，NR4A1是在之前筛选中鉴定的影响新冠病毒感染的候选基因。功能实验证实敲除NR4A1也可以使心肌细胞，肺泡类器官，气管类器官对新冠病毒的易感性降低。对RNA-seq数据进行信号通路富集分析发现，CIART敲除在各种细胞/类器官中抑制了RXR通路。qPCR检测发现NR4A1敲除同样下调了RXR信号通路相关基因。进一步用RXR通路的小分子抑制剂HX531和PA452处理各种细胞/类器官，同样发现新冠病毒感染被显著抑制。由于RXR通路在调控脂肪酸代谢中发挥重要作用，而已有报道显示抑制脂肪酸合成可以有效抑制新冠病毒感染，研究人员分析RNA-seq数据，发现CIART敲除或者HX531处理下调了多个脂肪酸代谢相关基因；代谢组学分析进一步确认CIART敲除或者HX531处理下调了多种脂肪酸的合成。总的来说，本研究系统分析了新冠病毒感染对人多能干细胞来源的多种细胞/类器官在转录组水平的影响，鉴定到多个影响新冠病毒感染的宿主基因，并具体研究了CIART影响新冠病毒感染的机理，揭示了CIART/NR4A1/RXR信号通路在调控新冠病毒感染中的重要作用。原文链接：https://www.nature.com/articles/s41556-023-01095-y会议推荐RECOMMENDATIONS点击了解详情会议信息大会时间：2023年5月19-20日大会地点：上海大会主题：前沿交叉创新融合扫描上方二维码或者点击【阅读原文】立即报名参会报名/媒体合作17321098232（微信同号）

基因疗法

2022-04-04

·生物制品圈

靶向EGFR药物neratinib的作用新机制

胶质母细胞瘤（glioblastoma, GBM）是成人最常见的一种恶性脑肿瘤，约占脑和其他中枢神经系统恶性肿瘤中的48.6%，目前缺乏有效的临床治疗手段，患者平均5年生存率只有7%，平均存活时间仅有12个月。临床基因组分析表明，在超过一半的GBM中发现了表皮生长因子受体（epidermal growth factor receptor, EGFR）基因改变，主要包括EGFR基因扩增和突变等功能获得性突变。虽然面向GBM通过靶向EGFR抑制进行了一系列药物研发，但是并未从根本上改善患者的生存率。除了GBM中的EGFR突变使药物会很快产生耐药外，其他耐药机制大多仍未明确，可能来自于药物对肿瘤组织的渗透不足，或是存在冗余的信号通路变化使得肿瘤细胞从EGFR激酶抑制的作用中逃逸。因此，寻找GBM中除了EGFR突变之外的反应信号传导或代谢途径，将有可能为克服耐药及联合治疗策略提供基础。基于此，来自美国的研究人员发展了基因组功能筛选的方法，并最终发现了靶向EGFR的药物neratinib作用的新通路及其机制。首先，研究人员利用泛ErbB激酶不可逆抑制剂neratinib处理EGFR突变的SF268 GBM细胞，结合全基因组CRISPR-KO筛选，从而富集发现了抗性靶标，如一般性调控阻遏蛋白2（general control nonderepressible 2，GCN2）的sgRNA EIF2AK4。研究发现，GCN2缺失会增强EGFR突变GBM细胞对neratinib的抗性，进一步在对人源TS895球型的GBM细胞进行体内和体外敲除GCN2后，也观察到对neratinib的抗性提高。在筛出了GCN2这一抗性基因后，为了探索neratinib通过GCN2发挥作用的下游信号通路，研究人员分析了筛选到的与neratinib抗性相关的其他基因：例如，GCN1，在整合应激反应（integrated stress response ，ISR）中可将不带氨基酸的tRNA结合到GCN2上并促进其磷酸化激活；其次，ATF4，作为ISR的另一个成员，该基因位于GCN2下游，细胞生长实验证实ATF4-KO能够增强对neratinib的抗性，免疫印迹实验也显示出了GCN2的激活和ATF4表达量的增加密切相关；除此之外，GADD34，作为该通路中的负调节因子，敲除GADD34会增强GBM细胞对neratinib的敏感性，细胞生长被抑制，促进细胞凋亡，而回补GADD34又会抑制细胞凋亡，增强药物抗性。综上，结合GCN2的结果，他们推导出neratinib在GBM细胞中除了抑制EGFR外，还会通过GCN2/ATF4通路的持续激活，从而促进细胞死亡。为了探究neratinib导致的EGFR抑制和GCN2激活之间的关联性，研究人员首先检测了两条通路的剂量反应关系，发现它们作用浓度无交叉且趋势无相关。此外，用EGFR下游效应蛋白抑制剂处理对GCN2通路无效应，不同细胞中不同的EGFR表达水平也与neratinib诱导的ATF4表达水平无关。值得注意的是，在对neratinib耐药的EGFR和HER2双突变细胞中，EGFR的激活不再受抑制而GCN2通路还是照样激活，这些证据都表明neratinib对EGFR抑制和GCN2激活两条通路的影响是无关联的。在排除了氨基酸缺乏导致GCN2通路信号激活的可能性后，研究人员猜测neratinib可能是直接结合并激活GCN2。因而，他们利用ATP替代实验发现neratinib会剂量依赖性与ATP竞争结合GCN2，且同位素标记ATP实验测得neratinib剂量依赖性激活GCN2的激酶活性，提示了neratinib直接结合GCN2并激活其活性。在此基础上，研究人员筛选了其他激酶抑制剂对GCN2激活的普适性。根据NIH LINCS KINOMEscan的数据，他们发现除了neratinib，还有其它一些激酶抑制剂会结合GCN2，例如erlotinib和gefitinib可以结合，但非可逆二代抑制剂的canertinib并不结合。为了分析这些不同类型的激酶抑制剂激活GCN2的原因，研究人员对EGFR结合neratinib和GCN2结合dovitinib的激酶结构域的晶体结构进行比对，提出neratinib可能是结合进GCN2的激酶结构域中不同区域从而关闭ATP结合口袋。为了阐明neratinib能激活GCN2激酶活性这一反常现象的机制，他们使用更大范围的抑制剂浓度进行体外放射性激酶活性实验，发现GCN2的活性是随着抑制剂浓度先增高后减弱，特别是在没有tRNA存在时也能激活GCN2。基于此，研究者提出：neratinib与GCN2二聚体中其一结合并诱导构象变化，稳定tRNA结合并通过未结合的单体导致酶活性增强，neratinib浓度的进一步增加导致两个激酶结构域都结合药物，最终导致GCN2激酶活性降低。综上，研究者通过全基因组功能筛选找到了靶向肿瘤EGFR突变的激酶抑制剂作用新机制，发现neratinib通过EGFR抑制和意料之外的GCN2激酶的激活来共同抑制肿瘤细胞生长和肿瘤细胞死亡，并提出了一个类似于RAF蛋白二聚体被其自身激酶抑制剂反式激活的模型，不过这种激酶抑制剂“脱靶”激活的效应是之前所没想到的，这种抑制剂激活激酶启动GCN2/ATF4轴的效应可能在未来的激酶抑制剂中得以应用以增强其抗肿瘤活性。参考文献 [1] Miller, K. D. , et al. "Brain and other central nervous system tumor statistics, 2021." CA: a cancer journal for clinicians 71.5:381-406. [2]An, et al. "Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies." Oncogene (2018). [3] Pan, P. C. , and R. S. Magge . "Mechanisms of EGFR Resistance in Glioblastoma." International Journal of Molecular Sciences 21.22(2020):1-21. [4]"GCN2 kinase activation by ATP-competitive kinase inhibitors." Nature Chemical Biology. [5] Poulikakos, P. I. , et al. "RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF." Nature 464.7287(2010):427-430. 内容来源于网络，如有侵权，请联系删除，谢谢。