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更新于：2025-05-07

RPRD1B

更新于：2025-05-07

基本信息

别名

C20orf77、Cell cycle-related and expression-elevated protein in tumor、CREPT

+ [9]

简介

Interacts with phosphorylated C-terminal heptapeptide repeat domain (CTD) of the largest RNA polymerase II subunit POLR2A, and participates in dephosphorylation of the CTD by RPAP2. Transcriptional regulator which enhances expression of CCND1. Promotes binding of RNA polymerase II to the CCDN1 promoter and to the termination region before the poly-A site but decreases its binding after the poly-A site. Prevents RNA polymerase II from reading through the 3' end termination site and may allow it to be recruited back to the promoter through promotion of the formation of a chromatin loop. Also enhances the transcription of a number of other cell cycle-related genes including CDK2, CDK4, CDK6 and cyclin-E but not CDKN1A, CDKN1B or cyclin-A. Promotes cell proliferation.

关联

项与 RPRD1B 相关的药物

CN118027205

专利挖掘

靶点

RPRD1B

作用机制-

在研机构

Heya (Beijing) Pharmaceutical Technology Co., Ltd

原研机构

Heya (Beijing) Pharmaceutical Technology Co., Ltd

在研适应症

肿瘤

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

CN115028738

专利挖掘

靶点

RPRD1B x TRIM21

作用机制-

在研机构

天津医科大学 [+1]

原研机构

天津医科大学 [+1]

在研适应症

内分泌系统疾病 [+1]

非在研适应症-

最高研发阶段药物发现

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 RPRD1B 相关的临床结果

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100 项与 RPRD1B 相关的转化医学

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0 项与 RPRD1B 相关的专利（医药）

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项与 RPRD1B 相关的文献（医药）

2025-01-01·Journal of Biological Chemistry

An oncoprotein CREPT functions as a co-factor in MYC-driven transformation and tumor growth

Article

作者: Wang, Xiaoguang ; Jiang, Guancheng ; Ren, Fangli ; Li, Mengdi ; Li, Jingya ; Jia, Jing ; Duan, Xiaolin ; He, Chunhua ; Li, Haitao ; Li, Meng ; Lin, Yuting ; Guan, Haipeng ; Wang, Yinyin ; Chang, Zhijie ; Cao, Chenxi ; Ma, Danhui

Understanding the mechanisms behind MYC-driven oncogenic transformation could pave the way for identifying novel drug targets. This study explored the role of CREPT in MYC-induced malignancy by generating MYC-transformed mouse embryonic fibroblasts (MEFs) with conditional CREPT deletion. Our results demonstrated that the loss of CREPT significantly impaired MYC-induced colony formation and cell proliferation, indicating that CREPT is essential for the malignant transformation of MEFs. Reintroducing CREPT in CREPT-deficient cells restored malignant properties. Furthermore, CREPT overexpression alone enhanced colony formation upon MYC induction but was insufficient to induce transformation without MYC, suggesting a cooperative interaction between CREPT and MYC in malignant transformation. CREPT deletion resulted in delayed cell cycle progression during the G2/M and S phases. CREPT enhanced the expression of MYC target genes by directly interacting with MYC through the CID domain of CREPT and the PEST domain of MYC. Arginine 34 of CREPT was identified as a critical residue for the interaction with MYC, and its mutation lost the ability of CREPT to promote MYC-driven colony formation and tumor growth in colorectal cancer models. Additionally, CREPT facilitated the recruitment of RNA Polymerase II to MYC-binding promoters, promoting transcriptional initiation of MYC-targeted genes. Our study also revealed a strong correlation between CREPT and MYC expression in various human cancers, particularly in colorectal cancer, where their interaction appears to play a significant role in tumorigenesis. These findings suggest that the CREPT-MYC interaction is crucial for the progression of MYC-driven cancers and presents a potential target for therapeutic intervention.

2024-08-01·eBioMedicine

A susceptibility gene signature for ERBB2-driven mammary tumour development and metastasis in collaborative cross mice

Article

作者: Corchado-Cobos, Roberto ; He, Li ; Mao, Jian-Hua ; Balmain, Allan ; Wang, Xinzhi ; Chang, Hang ; García-Sancha, Natalia ; Yang, Hui ; Wang, Pin ; Threadgill, David W ; Snijders, Antoine M ; Blanco-Gómez, Adrián ; Pérez-Baena, Manuel Jesús ; Perez-Losada, Jesus ; Inman, Jamie L ; Jiménez-Navas, Alejandro

BACKGROUNDDeeper insights into ERBB2-driven cancers are essential to develop new treatment approaches for ERBB2+ breast cancers (BCs). We employed the Collaborative Cross (CC) mouse model to unearth genetic factors underpinning Erbb2-driven mammary tumour development and metastasis.METHODS732 F1 hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains were monitored for mammary tumour phenotypes. GWAS pinpointed SNPs that influence various tumour phenotypes. Multivariate analyses and models were used to construct the polygenic score and to develop a mouse tumour susceptibility gene signature (mTSGS), where the corresponding human ortholog was identified and designated as hTSGS. The importance and clinical value of hTSGS in human BC was evaluated using public datasets, encompassing TCGA, METABRIC, GSE96058, and I-SPY2 cohorts. The predictive power of mTSGS for response to chemotherapy was validated in vivo using genetically diverse MMTV-Erbb2 mice.FINDINGSDistinct variances in tumour onset, multiplicity, and metastatic patterns were observed in F1-hybrid female mice between FVB/N MMTV-Erbb2 and 30 CC strains. Besides lung metastasis, liver and kidney metastases emerged in specific CC strains. GWAS identified specific SNPs significantly associated with tumour onset, multiplicity, lung metastasis, and liver metastasis. Multivariate analyses flagged SNPs in 20 genes (Stx6, Ramp1, Traf3ip1, Nckap5, Pfkfb2, Trmt1l, Rprd1b, Rer1, Sepsecs, Rhobtb1, Tsen15, Abcc3, Arid5b, Tnr, Dock2, Tti1, Fam81a, Oxr1, Plxna2, and Tbc1d31) independently tied to various tumour characteristics, designated as a mTSGS. hTSGS scores (hTSGSS) based on their transcriptional level showed prognostic values, superseding clinical factors and PAM50 subtype across multiple human BC cohorts, and predicted pathological complete response independent of and superior to MammaPrint score in I-SPY2 study. The power of mTSGS score for predicting chemotherapy response was further validated in an in vivo mouse MMTV-Erbb2 model, showing that, like findings in human patients, mouse tumours with low mTSGS scores were most likely to respond to treatment.INTERPRETATIONOur investigation has unveiled many new genes predisposing individuals to ERBB2-driven cancer. Translational findings indicate that hTSGS holds promise as a biomarker for refining treatment strategies for patients with BC.FUNDINGThe U.S. Department of Defense (DoD) Breast Cancer Research Program (BCRP) (BC190820), United States; MCIN/AEI/10.13039/501100011039 (PID2020-118527RB-I00, PDC2021-121735-I00), the "European Union Next Generation EU/PRTR," the Regional Government of Castile and León (CSI144P20), European Union.

2024-05-08·Nucleic Acids Research

Identifying human pre-mRNA cleavage and polyadenylation factors by genome-wide CRISPR screens using a dual fluorescence readthrough reporter

Article

作者: Chan, Katherine ; Burke, Giovanni L ; Moffat, Jason ; Guo, Xinghua ; Greenblatt, Jack F ; Blencowe, Benjamin J ; Song, Jingwen ; Marcon, Edyta ; Ha, Kevin C H ; Tong, Amy Hin Yan ; Nabeel-Shah, Syed ; Pu, Shuye ; Ni, Zuyao ; Ahmed, Nujhat

AbstractMessenger RNA precursors (pre-mRNA) generally undergo 3′ end processing by cleavage and polyadenylation (CPA), which is specified by a polyadenylation site (PAS) and adjacent RNA sequences and regulated by a large variety of core and auxiliary CPA factors. To date, most of the human CPA factors have been discovered through biochemical and proteomic studies. However, genetic identification of the human CPA factors has been hampered by the lack of a reliable genome-wide screening method. We describe here a dual fluorescence readthrough reporter system with a PAS inserted between two fluorescent reporters. This system enables measurement of the efficiency of 3′ end processing in living cells. Using this system in combination with a human genome-wide CRISPR/Cas9 library, we conducted a screen for CPA factors. The screens identified most components of the known core CPA complexes and other known CPA factors. The screens also identified CCNK/CDK12 as a potential core CPA factor, and RPRD1B as a CPA factor that binds RNA and regulates the release of RNA polymerase II at the 3′ ends of genes. Thus, this dual fluorescence reporter coupled with CRISPR/Cas9 screens reliably identifies bona fide CPA factors and provides a platform for investigating the requirements for CPA in various contexts.

项与 RPRD1B 相关的新闻（医药）

2022-10-18

·生物谷

J Exp Clin Cancer Res: 长非编码RNA NEAT1介导的RPRD1B稳定性促进胃癌c-jun/c-Fos/SREBP1轴的脂肪酸代谢和淋巴结转移

胃癌是全球第四大常见癌症，也是第二大癌症相关死亡原因。作为导致癌症相关死亡的罪魁祸首，转移是我们与癌症这一威胁生命的疾病作斗争的终极挑战。胃癌是全球第四大常见癌症，也是第二大癌症相关死亡原因。作为导致癌症相关死亡的罪魁祸首，转移是我们与癌症这一威胁生命的疾病作斗争的终极挑战。胃癌患者的淋巴结转移与肿瘤侵袭性密切相关，预后较差。根据越来越多的证据，淋巴结转移是癌细胞进一步扩散的来源，表明淋巴结转移的机制是非常重要的。然而，以往对肿瘤转移的研究大多集中在远处转移的机制上，而对淋巴结转移的研究较少。导致肿瘤淋巴转移的分子驱动因素仍不清楚。器官趋向性方面的器官特异性转移在很大程度上取决于固有的癌细胞属性的作用，如驱动基因和调控定植的途径，以及特定器官的转移前微环境。图片来源：https://doi.org/10.1186/s13046-022-02449-4 近日，来自郑州大学的研究者们在J Exp Clin Cancer Res杂志上发表了题为“Long non-coding RNA NEAT1 mediated RPRD1B stability facilitates fatty acid metabolism and lymph node metastasis via c-Jun/c-Fos/SREBP1 axis in gastric cancer”的文章，该研究证实了RPRD1B通过c-jun/c-Fos/SREBP1轴促进FA代谢，并通过NEAT1介导的正反馈环促进原发肿瘤在淋巴结中的种植，成为GC治疗的潜在治疗靶点。淋巴结转移是影响胃癌分期和预后的最常见因素之一。然而，介导淋巴结转移的关键分子事件和机制仍然不清楚。应用RNA测序技术对4例胃原发肿瘤、淋巴结转移灶和配对的正常胃上皮组织中与淋巴结转移相关的驱动基因进行了分析。采用定量逆转录聚合酶链式反应和免疫组织化学方法检测RPRD1B的表达。在体外和体内对转移功能进行评估。用RNA-seq方法鉴定目的基因。芯片、EMSA和双荧光素酶报告分析鉴定靶基因的结合部位。应用Co-IP、RIP、MERIP、RNA-FISH和泛素分析探讨其可能的作用机制。筛选在胃癌患者转移淋巴结中显著上调的前8个靶基因(RPRD1B、MAP4K4、MCM2、TOPBP1、FRMD8、KBTBD2、ADAM10和CXCR4)。选择转录辅因子RPRD1B(含有1B的核前mRNA结构域的调节)进行进一步的鉴定。临床分析表明，RPRD1B在转移的淋巴结中显著过表达，并与GC患者的预后不良有关。METTL3诱导的M6A修饰参与了RPRD1B的上调。在功能上，RPRD1B在体外和体内都促进了淋巴结转移能力。机制研究表明，RPRD1B通过在转录水平上调c-Jun/c-Fos和激活c-Jun/c-Fos/SREBP1轴来增加脂肪酸的摄取和合成。此外，在RPRD1B过表达细胞中，c-jun/c-Fos显著上调了NEAT1的表达。而NEAT1则通过招募m6A“阅读器”蛋白hnRNPA2B1来增加RPRD1B mRNA的稳定性，并通过抑制TRIM25介导的泛素化来减少RPRD1B蛋白的降解。但是，c-jun/c-Fos/AP1蛋白的抑制剂(SR11302)和针对NEAT1的小干扰RNA破坏了这一功能回路，导致了对淋巴结转移的优先损害。 RPRD1B在胃癌淋巴转移中的作用机制示意图图片来源：https://doi.org/10.1186/s13046-022-02449-4 总体而言，本研究确认m6A诱导的RPRD1B过度表达是胃癌淋巴转移的始动事件。RPRD1B进一步激活了c-jun/c-Fos/SREBP1轴，上调了一组与脂肪酸吸收和合成相关的基因(ACSS2、FASN和FABP3)，并促进了GC细胞在淋巴结中的转移。这些发现为转录因子、lncRNAs和蛋白质之间的协调相互作用在胃癌淋巴转移中的重要性提供了新的见解。更好地了解RPRD1B在淋巴结转移中的致癌机制可能会导致开发新的胃癌治疗策略。（生物谷 Bioon.com）参考文献 Yongxu Jia et al. Long non-coding RNA NEAT1 mediated RPRD1B stability facilitates fatty acid metabolism and lymph node metastasis via c-Jun/c-Fos/SREBP1 axis in gastric cancer. J Exp Clin Cancer Res. 2022 Sep 29;41(1):287. doi: 10.1186/s13046-022-02449-4.

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