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更新于：2025-05-07

HNRNPK

更新于：2025-05-07

基本信息

别名

CSBP、heterogeneous nuclear ribonucleoprotein K、hnRNP K

+ [4]

简介

One of the major pre-mRNA-binding proteins. Binds tenaciously to poly(C) sequences. Likely to play a role in the nuclear metabolism of hnRNAs, particularly for pre-mRNAs that contain cytidine-rich sequences. Can also bind poly(C) single-stranded DNA. Plays an important role in p53/TP53 response to DNA damage, acting at the level of both transcription activation and repression. When sumoylated, acts as a transcriptional coactivator of p53/TP53, playing a role in p21/CDKN1A and 14-3-3 sigma/SFN induction (By similarity). As far as transcription repression is concerned, acts by interacting with long intergenic RNA p21 (lincRNA-p21), a non-coding RNA induced by p53/TP53. This interaction is necessary for the induction of apoptosis, but not cell cycle arrest. As part of a ribonucleoprotein complex composed at least of ZNF827, HNRNPL and the circular RNA circZNF827 that nucleates the complex on chromatin, may negatively regulate the transcription of genes involved in neuronal differentiation (PubMed:33174841).

关联

靶点

HNRNPK

作用机制

HNRNPK inhibitors

在研机构

The University of Texas MD Anderson Cancer Center

原研机构

The University of Texas MD Anderson Cancer Center

在研适应症

血液肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 HNRNPK 相关的临床结果

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100 项与 HNRNPK 相关的转化医学

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0 项与 HNRNPK 相关的专利（医药）

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项与 HNRNPK 相关的文献（医药）

2025-06-01·Neurobiology of Disease

ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation

Article

作者: Key, Jana ; Meierhofer, David ; Gispert, Suzana ; Auburger, Georg ; Almaguer-Mederos, Luis-Enrique ; Kandi, Arvind Reddy ; Sen, Nesli-Ece ; Köpf, Gabriele

The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, Atxn2-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.

2025-05-01·Brain Pathology

hnRNP A1, hnRNP A2B1, and hnRNP K are dysregulated in tauopathies, but do not colocalize with tau pathology

Article

作者: Drummond, Eleanor ; Lourenco, Guinevere F. ; Kavanagh, Tomas ; Balcomb, Kaleah ; Halliday, Glenda ; Ahmadi Rastegar, Diba ; Wisniewski, Thomas

AbstractTau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)—a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8‐immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.

2025-05-01·International Journal of Biological Macromolecules

The glutamine starvation-induced lncRNA FERRIN suppresses ferroptosis via the stabilization of SLC7A11 mRNA

Article

作者: Mei, Yide ; Guo, Xiaorui ; Wang, Fang ; Wang, Zhongyu ; Wu, Xianning ; Luo, Jingjing ; Liu, Kaiyue

As an essential nutrient for cancer cell survival, glutamine plays both promoting and inhibitory roles in ferroptosis; however, the underlying mechanisms remain obscure. Emerging evidence suggests that long noncoding RNAs (lncRNAs) are crucial regulators of ferroptosis. Nevertheless, it remains unclear whether lncRNAs are involved in glutamine-regulated ferroptosis. In this study, we report that the lncRNA FERRIN is induced by the transcription factor ATF4 under glutamine starvation conditions. FERRIN functions as an inhibitor of ferroptosis by upregulating SLC7A11 expression. Mechanistically, FERRIN interacts with the RNA binding protein hnRNPK, facilitating its binding to SLC7A11 mRNA and leading to the stabilization of SLC7A11 mRNA. Consistent with its inhibitory role in ferroptosis, FERRIN promotes in vitro cancer cell proliferation and in vivo xenograft tumor growth through its modulation of SLC7A11. Collectively, these findings establish FERRIN as a critical negative regulator of ferroptosis and suggest that FERRIN may represent an important link between glutamine availability and ferroptosis.

项与 HNRNPK 相关的新闻（医药）

2024-04-30

·生物探索

J Hepatol | 空军军医大学陶开山/贾林涛发现肝内胆管癌的发病新机理

引言肝内胆管癌(iCCA)是一种致命的胆道系统恶性肿瘤。缺乏对致癌信号或全局基因表达改变的详细了解阻碍了临床iCCA的诊断和治疗。蛋白乳酸化作用是一种新近发现的协调基因表达的翻译后修饰，在iCCA的发病机制中仍然难以捉摸。2024年4月26日，空军军医大学陶开山及贾林涛共同通讯在Journal of Hepatology（IF 26）在线发表题为“Nucleolin lactylation contributes to intrahepatic cholangiocarcinoma pathogenesis via RNA splicing regulation of MADD ”的研究论文，该研究表明核蛋白乳酸化通过RNA剪接调控MADD参与肝内胆管癌的发病。核蛋白(Nucleolin, NCL)是核核中最丰富的RNA结合蛋白，被认为是与iCCA发生和发展相关的功能性乳酸化靶点。在糖酵解过度活跃的情况下，NCL主要在赖氨酸477位点被酰基转移酶P300乳酸化，并促进iCCA细胞的增殖和侵袭。在机制上，乳酸化的NCL结合到MAP激酶激活死亡结构域蛋白(MADD)的初级转录本上，并通过避免产生过早终止密码子的选择性剪接来保证MADD的有效翻译。NCL乳酸化、MADD和随后的ERK激活促进了异种移植物肿瘤的生长，并被发现与iCCA患者的总生存率相关。总之，NCL通过RNA剪接依赖机制乳酸化上调MADD，从而通过MAPK途径增强iCCA的发病机制。肝内胆管癌(iCCA)是一种罕见的原发性、高度侵袭性的肝脏恶性肿瘤，起源于肝内和肝外胆管上皮细胞。尽管世界范围内的发病率不断上升，但由于缺乏潜在的治疗选择，迄今为止，对iCCA进行最佳诊断和管理仍然是一项艰巨的挑战。虽然大多数iCCA是新发的，没有可识别的危险因素，但染色体突变已被定位到典型的癌症相关基因座，包括KRAS、TP53、IDH1/2、BAP1、MDM2和FGFR2，这些基因座导致致癌信号的过度活跃，例如MAPK和PI3K/AKT通路。这些遗传改变最终通过CDX2、TTF1、GATA3和PAX8等转录因子的异常激活导致基因的广泛失调。然而，越来越多的研究表明，在iCCA的发展过程中，除基因转录调控外，其他机制也发挥着不可或缺的作用。特别是，在pre-mRNA成熟过程中的选择性剪接(AS)，这是由于产生或破坏剪接位点的突变，剪接因子的异常表达以及影响剪接事件活性的信号通路受损，已经被证实能够微调iCCA的基因表达谱。此外，翻译后修饰，如FGFRs或hnRNP-K的糖基化和BAP1等关键调控因子的泛素化/去泛素化，也被证明是iCCA发病机制的基础，增加了异常基因表达的分层和多级调控的复杂性。在过去的3年里，人们发现了一种新型的翻译后修饰—蛋白质乳酸化，它参与了各种生理和病理过程。在组蛋白上，赖氨酸残基上添加乳酸基首次被报道，这代表了一种驱动基因转录的新型表观遗传模式。然而，后来发现所谓的赖氨酸乳酸化在非组蛋白中普遍存在。乳酸化最常见的供体是糖酵解的最终产物乳酸盐，因此将其从代谢废物或能量来源重新定义为基因表达和蛋白质功能的关键调节剂。乳酸化蛋白分布在多个亚细胞区室中，并与多种生物过程密切相关，包括mRNA剪接、糖酵解、氨基酰基- tRNAs生物合成、RNA转运和许多信号通路。因此，蛋白质乳酸化已被确定在炎症、神经发育和肿瘤发展中发挥重要作用。在肿瘤发生的情况下，乳酸化也可能在代谢重编程和复杂的信号网络之间提供直接联系，这些信号网络是基因解除管制和癌症特征的基础。然而，大多数恶性肿瘤的乳酸酶仍有待研究，蛋白质乳酸化在癌症发生和进展中的作用在很大程度上仍然难以捉摸。模式图（Credit: Journal of Hepatology）该研究使用质谱分析筛选临床iCCA和癌旁组织之间的差异乳酸化蛋白，并鉴定出核蛋白(NCL)是一种促进胆管癌的新型乳酸化底物。从机制上讲，NCL在赖氨酸477上的乳酸化是抑制MAP激酶激活死亡结构域蛋白(MADD)转录本的选择性5 '剪接的活性所必需的，这种剪接会导致蛋白质合成的不期望终止。因此，乳酸化的NCL上调MADD，MADD作为一个接体蛋白随后将来自跨膜受体的信号传递给有丝分裂原激活蛋白激酶(MAPK)并促进iCCA的发展。该研究结果揭示了代谢重编程和典型肿瘤启动事件之间的新联系，并提供了可能用于预后评估或靶向治疗iCCA的生物标志物。原文链接https://doi.org/10.1016/j.jhep.2024.04.010责编|探索君排版|探索君文章来源|“iNature”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Nature | 破除传统：为何我们需要重新思考肿瘤的命名方式热文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

信使RNA

2023-08-24

·生物谷

中国科技大学研究者们揭示了MGCG有可能促进恶性胶质瘤的发展，并可能成为肿瘤分子诊断和治疗的候选分子

成人胶质母细胞瘤(GBM)是最致命、最顽固的恶性实体瘤之一。根据世界卫生组织(WHO)的病理分类，GBM分为数字分级(I-IV)。GBM被认为是不可治愈的，经过积极的综合治疗成人胶质母细胞瘤(GBM)是最致命、最顽固的恶性实体瘤之一。根据世界卫生组织(WHO)的病理分类，GBM分为数字分级(I-IV)。GBM被认为是不可治愈的，经过积极的综合治疗，包括最安全的手术切除和辅助放射治疗(RT)，同时辅以替莫唑胺(TMZ)治疗，中位生存期为15个月。目前，标准磁共振成像为GBM的初步检测提供了最敏感的工具。然而，当通过成像识别出GBM可定义的病变时，肿瘤处于晚期状态。因此，在GBM的发生和发展过程中，必须进行分子诊断，尤其是各种生物标志物的研究。图片来源：https://doi.org/10.1038/s41419-023-05959-x 近日来自中国科技大学的研究者们在Cell Death and Disease杂志上发表了题为“MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy”的文章，该研究揭示了MGCG通过hnRNPK/ATG2A调节胶质母细胞瘤的致瘤性并促进自噬。胶质母细胞瘤(GBM)是成人最常见的恶性原发脑癌，一直是研究的热点。长非编码RNA(LncRNAs)在肿瘤的发生发展中起着重要作用。为了阐明lncRNAs在胶质母细胞瘤发生发展中的作用，研究者采用高通量RNA测序技术获得了来自GBM患者的3个新鲜分离的肿瘤组织和3个患者创伤性脑组织的转录本。后来，一种在胶质母细胞瘤中高水平表达的lncRNA MGCG(MGC70870在胶质母细胞瘤中高水平表达)被发现与患者的预后有关，这在胶质母细胞瘤中尚未见报道。生物信息学分析结果表明，MGCG与自噬相关，并与自噬相关基因ATG2A的表达呈正相关。质谱学分析表明，hnRNPK蛋白是与MGCG相互作用的直接靶点，MGCG/hnRNPK通过促进ATG2A的翻译和自噬促进了GBM的发展。综上所述，本研究表明MGCG有可能促进GBM的发展，并可能成为肿瘤分子诊断和治疗的候选分子。 MGCG在体内和临床样本中促进GBM组织的进展图片来源：https://doi.org/10.1038/s41419-023-05959-x 研究者发现了一种新的长非编码RNA MGCG，它作为癌基因促进GBM的增殖和迁移。接下来，研究者验证了MGCG与自噬相关。研究者证明了MGCG直接与hnRNPK结合，MGCG/hnRNPK促进了ATG2A的翻译。因此，本研究揭示了长非编码RNA调节GBM生长的机制，并确定了治疗GBM的潜在治疗药物靶点。（生物谷 Bioon.com）参考文献 Fang Chu et al. MGCG regulates glioblastoma tumorigenicity via hnRNPK/ATG2A and promotes autophagy. Cell Death Dis. 2023 Jul 17;14(7):443. doi: 10.1038/s41419-023-05959-x.

临床研究

2023-07-21

·生物谷

暨南大学研究者为乳腺癌的治疗提供了新的潜在靶点和候选药物

乳腺癌是女性最常见的恶性肿瘤之一。肿瘤转移是实体瘤患者死亡的重要原因。许多文章报道了选择性剪接在乳腺癌中的重要作用。乳腺癌是女性最常见的恶性肿瘤之一。肿瘤转移是实体瘤患者死亡的重要原因。许多文章报道了选择性剪接在乳腺癌中的重要作用。Hahn等人。发现QKI和RBFOX1协同调节编码肌动蛋白结合蛋白FLNB的基因的剪接，从而诱导乳腺癌的上皮-间充质转化(EMT)。在MCF-7和MDA-MB-231细胞中敲除HNRNPF、HNRNPH1和HNRNPK可促进促凋亡基因Mcl-1s(跳过外显子2)的表达，进而促进癌细胞的凋亡，延缓乳腺癌的发展。图片来源：https://doi.org/10.1038/s41401-023-01116-4 近日，来自暨南大学的研究者们在Acta Pharmacologica Sinica杂志上发表了题为“Truncated SCRIB isoform promotes breast cancer metastasis through HNRNP A1 mediated exon 16 skipping”的文章，该研究为乳腺癌的治疗提供了新的潜在靶点和候选药物。乳腺癌是最常见的恶性肿瘤之一，其转移性死亡率较高。Scrib是一种主要分布在细胞膜上的支架蛋白，是一种潜在的肿瘤抑制因子。Scrib的错误定位和异常表达可刺激EMT通路，促进肿瘤细胞转移。Scrib有两种通过选择性剪接产生的亚型(带或不带外显子16)。在本研究中，研究者研究了Scrib亚型在乳腺癌转移中的作用及其调控机制。我们发现，与全长异构体(Scrib-L)相比，截短的Scrib异构体(Scrib-S)在高转移的MDA-MB-231细胞中过表达，该细胞通过激活ERK通路促进乳腺癌转移。Scrib-S对催化磷酸酶亚单位PPP1CA的亲和力低于Scrib-L，这可能是两种异构体在肿瘤转移中作用不同的原因之一。通过基于CLIP、RIP和MS2-GFP的实验，研究者发现异质核糖核蛋白A1(HnRNP A1)通过与Scrib内含子15上富含AG的序列caggauggaggccccccgugccgag结合，促进了Scrib外显子16的跳跃。根据该结合序列设计的Scrib反义寡核苷酸(ASO-Scrib)转染MDAMB-231细胞，不仅有效地抑制了hnRNPA1与Scrib Pre-MRNA的结合，抑制了Scrib-S的产生，而且逆转了hnRNPA1激活ERK通路，抑制了乳腺癌的转移。 HnRNP A1调节Scrib外显子16跳跃促进乳腺癌转移图片来源：https://doi.org/10.1038/s41401-023-01116-4 综上所述，本研究表明hnRNP A1调控Scrib的选择性剪接，并促进SCRIBS的产生，从而增加乳腺癌细胞的转移能力。这些结果是RRM基序缺失的结果，该基序丧失了hnRNPA1准确识别Scrib prem RNA的能力或抑制Scrib-S的形成，从而促进乳腺癌的转移。此外，ASO-Scrib有效地抑制了hnRNP A1对Scrib选择性剪接的调节，从而抑制了乳腺癌细胞的侵袭和迁移。因此，hnRNPA1对Scrib选择性剪接的调控是治疗乳腺癌转移的一种有前途的策略。（生物谷 Bioon.com）参考文献 Bin Zhang et al. Truncated SCRIB isoform promotes breast cancer metastasis through HNRNP A1 mediated exon 16 skipping. Acta Pharmacol Sin. 2023 Jul 4. doi: 10.1038/s41401-023-01116-4.

临床研究信使RNA临床终止临床结果