更新于：2024-09-19

WDR77

更新于：2024-09-19

基本信息

别名

Androgen receptor cofactor p44、MEP-50、MEP50

+ [7]

简介

Non-catalytic component of the methylosome complex, composed of PRMT5, WDR77 and CLNS1A, which modifies specific arginines to dimethylarginines in several spliceosomal Sm proteins and histones (PubMed:11756452). This modification targets Sm proteins to the survival of motor neurons (SMN) complex for assembly into small nuclear ribonucleoprotein core particles. Might play a role in transcription regulation. The methylosome complex also methylates the Piwi proteins (PIWIL1, PIWIL2 and PIWIL4), methylation of Piwi proteins being required for the interaction with Tudor domain-containing proteins and subsequent localization to the meiotic nuage (PubMed:23071334).

关联

靶点

PRMT5 x WDR77

作用机制

PRMT5抑制剂 [+1]

在研机构

Purdue University [+1]

原研机构

Purdue University [+1]

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

100 项与 WDR77 相关的临床结果

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100 项与 WDR77 相关的转化医学

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0 项与 WDR77 相关的专利（医药）

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118

项与 WDR77 相关的文献（医药）

2024-08-01·Journal of Experimental Zoology Part A: Ecological and Integrative Physiology

Maternal methylosome protein 50 is essential for embryonic development in medaka Oryzias latipes

Article

作者: Hong, Wentao ; Zhong, Xueping ; Zhou, Qingchun ; Zhao, Haobin ; Li, Zhenyu ; Wu, Fan ; Cao, Mengxi ; Chen, Xinhua ; Duan, Shi ; Yang, Qing

AbstractMethylosome protein 50 (Mep50) is a protein that is rich in WD40 domains, which mediate and regulate a variety of physiological processes in organisms. Previous studies indicated the necessity of Mep50 in embryogenesis in mice Mus musculus and fish. This study aimed to further understand the roles of maternal Mep50 in early embryogenesis using medaka Oryzias latipes as a model. Without maternal Mep50, medaka zygotes developed to the pre‐early gastrula stage but died later. The transcriptome of the embryos at the pre‐early gastrula stage was analyzed by RNA sequencing. The results indicated that 1572 genes were significantly upregulated and 741 genes were significantly downregulated in the embryos without maternal Mep50. In the differentially expressed genes (DEGs), the DNA‐binding proteins, such as histones and members of the small chromosome maintenance complex, were enriched. The major interfered regulatory networks in the embryos losing maternal Mep50 included DNA replication and cell cycle regulation, AP‐1 transcription factors such as Jun and Fos, the Wnt pathway, RNA processing, and the extracellular matrix. Quantitative RT‐PCR verified 16 DEGs, including prmt5, H2A, cpsf, jun, mcm4, myc, p21, ccne2, cdk6, and col1, among others. It was speculated that the absence of maternal Mep50 could potentially lead to errors in DNA replication and cell cycle arrest, ultimately resulting in cell apoptosis. This eventually resulted in the failure of gastrulation and embryonic death. The results indicate the importance of maternal Mep50 in early embryonic development, particularly in medaka fish.

2024-06-14·Oncogene

Arginine methylation of caspase-8 controls life/death decisions in extrinsic apoptotic networks

Article

作者: Seyrek, Kamil ; Lavrik, Inna N ; König, Corinna ; Pietkiewicz, Sabine ; Ivanisenko, Nikita V ; Kähne, Thilo ; Wohlfromm, Fabian

AbstractProcaspase-8 is a key mediator of death receptor (DR)-mediated pathways. Recently, the role of post-translational modifications (PTMs) of procaspase-8 in controlling cell death has received increasing attention. Here, using mass spectrometry screening, pharmacological inhibition and biochemical assays, we show that procaspase-8 can be targeted by the PRMT5/RIOK1/WD45 methylosome complex. Furthermore, two potential methylation sites of PRMT5 on procaspase-8, R233 and R435, were identified in silico. R233 and R435 are highly conserved in mammals and their point mutations are among the most common mutations of caspase-8 in cancer. The introduction of mutations at these positions resulted in inhibitory effects on CD95L-induced caspase-8 activity, effector caspase activation and apoptosis. In addition, we show that procaspase-8 can undergo symmetric di-methylation. Finally, the pharmacological inhibition of PRMT5 resulted in the inhibitory effects on caspase activity and apoptotic cell death. Taken together, we have unraveled the additional control checkpoint in procaspase-8 activation and the arginine methylation network in the extrinsic apoptosis pathway.

2024-06-01·Comparative Biochemistry and Physiology Part D: Genomics and Proteomics

Methylosome protein 50 is necessary for oogenesis in medaka

Article

作者: Duan, Shi ; Wu, Fan ; Yao, Qiting ; Zhong, Xueping ; Zhou, Qingchun ; Zhao, Haobin ; Cao, Mengxi ; Chen, Xinhua ; Li, Zhenyu ; Yang, Qing

Methylosome protein 50 (Mep50) functions as a partner to protein arginine methyltransferase 5. MEP50 serves as a coactivator for both the androgen receptor and estrogen receptor in humans. Mep50 plays a crucial role in the development of germ cells in Drosophila. The precise role of Mep50 in oogenesis remains unclear in vertebrates. The objective of this study was to investigate the role of Mep50 in oogenesis in medaka fish. Disruption of Mep50 resulted in impaired oogenesis and the formation of multiple oocyte follicles in medaka. RNA-seq analysis revealed significant differential gene expression in the mutant ovary, with 4542 genes up-regulated and 1264 genes down-regulated. The regulated genes were found to be enriched in cellular matrices and ECM-receptor interaction, the Notch signaling pathway, the PI3K-Akt signaling pathway, the MAPK signaling pathway, the Hippo signaling pathway, and the Jak-Stat pathway, among others. In addition, the genes related to the hypothalamus-pituitary-gonad axis, steroid metabolism, and IGF system were impacted. Furthermore, the mutation of mep50 caused significant alterations in alternative splicing of pre-mRNA in ovarian cells. Quantitative RT-PCR results validated the findings from RNA-seq analysis in the specific genes, including akt2, map3k5, yap1, fshr, cyp17a, igf1, ythdc2, cdk6, and col1, among others. The findings of this study demonstrate that Mep50 plays a crucial role in oogenesis, participating in a diverse range of biological processes such as steroid metabolism, cell matrix regulation, and signal pathways. This may be achieved through the regulation of gene expression via mRNA splicing in medaka ovarian cells.