Map4k1-KO 基因敲除小鼠

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产品名称

Map4k1-KO 基因敲除小鼠

产品编号

S-KO-08494

品系全称

C57BL/6JCya-Map4k1em1/Cya

品系背景

C57BL/6JCya

品系编号

KOCMP-26411-Map4k1-B6J-VA

品系状态

使用本品系发表的文献需注明: Map4k1-KO 基因敲除小鼠 mice (Strain S-KO-08494) were purchased from Cyagen.
交付类型
周龄
性别
基因型
数量
KO小鼠库模型
MAPK信号通路

基本信息

基因研究概述

质控标准

基因
基因全称
mitogen-activated protein kinase kinase kinase kinase 1
基因别称
Hpk1,mHPK1
染色体号
Chr 7 (Mouse)
转录本 ID
NCBI: NM_008279 | Ensembl: ENSMUST00000085835
修饰方式
全身性基因敲除
靶向范围
Exon 5~20
敲除长度
~9.9 kb
品系说明
该品系是基于策略设计时的数据库信息制作而成,建议您在购买前查询最新的数据库和相关文献,以获取最准确的表型信息。
表型提示
MGI:1346882Homozygous null mice have increased responses of B and T cells. Dendritic cells are also hyperresponsive to stimulation.
Map4k1,也称为MAP4K1,是一种编码HPK1(hematopoietic progenitor kinase 1)的基因。HPK1是一种丝氨酸/苏氨酸激酶,属于MAP4K家族,是MAPK信号通路的上游调控因子。MAPK信号通路在细胞增殖、分化、凋亡和炎症反应等过程中发挥重要作用。HPK1通过磷酸化下游的MAP3Ks(如MLK3和MKK4)来激活JNK(c-Jun N-terminal kinase)和p38 MAPK信号通路,进而影响细胞生物学行为。研究表明,HPK1在多种疾病中发挥重要作用,包括癌症、自身免疫性疾病和心血管疾病。

研究发现,Map4k1高表达与T细胞功能障碍相关。在多种癌症类型中,Map4k1高表达与T细胞耗竭程度增加和患者生存率下降相关[1]。Map4k1基因敲除小鼠的肿瘤生长速度慢于野生型小鼠,浸润的T细胞耗竭程度低,活性和增殖能力强。此外,Map4k1的基因耗竭、药理学抑制或PROTAC介导的降解可以提高CAR-T细胞免疫疗法的疗效[1]。

Pdcd4(programmed cell death 4)是一种肿瘤抑制因子,其表达在多种癌症类型中下调。研究表明,Pdcd4的敲低上调了Map4k1的表达和c-Jun的磷酸化,而c-Myc的过表达也增加了Map4k1的表达和AP-1依赖性转录活性[2]。此外,Pdcd4过表达的结肠癌细胞中,Map4k1的表达被抑制,c-Jun的激活被阻断,肿瘤细胞的侵袭能力降低[3]。

RNA-Seq基因表达分析表明,Map4k1在宫颈癌中表达上调,且与患者生存率相关[4]。DLX6-AS1在胃癌中表达上调,通过FUS调节Map4k1的表达,促进胃癌细胞的增殖、迁移和EMT过程[5]。此外,Map4k1还与膀胱癌的进展相关,可以作为预测肿瘤进展的指标[6]。

SPIB转录因子在结直肠癌细胞中发挥肿瘤抑制作用。SPIB通过激活NFκB和JNK信号通路,上调Map4k1的表达,抑制肿瘤细胞的增殖、迁移和侵袭[7]。lncRNA CDKN2B-AS1与转录因子BCL11A相互作用,调节Map4k1的转录,影响Treg细胞的增殖和IL-4、IL-10和TGF-β的表达,进而影响脑梗死的发生发展[8]。

Map4k1还与系统性红斑狼疮(SLE)相关。HPK1(Map4k1编码的蛋白质)和DUSP22在SLE患者的T细胞中下调,而MAP4K3和DUSP4在SLE患者的T细胞中上调,表明Map4k1及其相关信号通路在SLE的发生发展中发挥重要作用[9]。此外,Map4k1还与视网膜血管扭曲度相关,影响心血管疾病的发生发展[10]。

综上所述,Map4k1在多种疾病中发挥重要作用,包括癌症、自身免疫性疾病和心血管疾病。Map4k1通过调节MAPK信号通路影响细胞生物学行为,其表达水平与疾病的发生发展和患者预后相关。研究Map4k1的生物学功能和调控机制,有助于深入理解疾病发生发展的分子机制,为疾病的治疗和预防提供新的思路和策略。

参考文献:
1. Si, Jingwen, Shi, Xiangjun, Sun, Shuhao, Wei, Lai, Liao, Xuebin. 2020. Hematopoietic Progenitor Kinase1 (HPK1) Mediates T Cell Dysfunction and Is a Druggable Target for T Cell-Based Immunotherapies. In Cancer cell, 38, 551-566.e11. doi:10.1016/j.ccell.2020.08.001. https://pubmed.ncbi.nlm.nih.gov/32860752/
2. Wang, Qing, Zhang, Yan, Yang, Hsin-Sheng. 2012. Pdcd4 knockdown up-regulates MAP4K1 expression and activation of AP-1 dependent transcription through c-Myc. In Biochimica et biophysica acta, 1823, 1807-14. doi:10.1016/j.bbamcr.2012.07.004. https://pubmed.ncbi.nlm.nih.gov/22801218/
3. Yang, Hsin-Sheng, Matthews, Connie P, Clair, Timothy, Tan, Tse-Hua, Colburn, Nancy H. . Tumorigenesis suppressor Pdcd4 down-regulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. In Molecular and cellular biology, 26, 1297-306. doi:. https://pubmed.ncbi.nlm.nih.gov/16449643/
4. Livesey, Michelle, Rossouw, Sophia Catherine, Blignaut, Renette, Christoffels, Alan, Bendou, Hocine. 2023. Transforming RNA-Seq gene expression to track cancer progression in the multi-stage early to advanced-stage cancer development. In PloS one, 18, e0284458. doi:10.1371/journal.pone.0284458. https://pubmed.ncbi.nlm.nih.gov/37093793/
5. Wu, Qiong, Ma, Jiali, Meng, Wenying, Hui, Pingping. 2019. DLX6-AS1 promotes cell proliferation, migration and EMT of gastric cancer through FUS-regulated MAP4K1. In Cancer biology & therapy, 21, 17-25. doi:10.1080/15384047.2019.1647050. https://pubmed.ncbi.nlm.nih.gov/31591939/
6. van der Heijden, Antoine G, Mengual, Lourdes, Lozano, Juan J, Alcaraz, Antonio, Witjes, J Alfred. 2016. A five-gene expression signature to predict progression in T1G3 bladder cancer. In European journal of cancer (Oxford, England : 1990), 64, 127-36. doi:10.1016/j.ejca.2016.06.003. https://pubmed.ncbi.nlm.nih.gov/27414486/
7. Zhao, Xunping, Li, Lin, Yuan, Shiyun, Jiang, Xianyao, Luo, Tao. 2021. SPIB acts as a tumor suppressor by activating the NFkB and JNK signaling pathways through MAP4K1 in colorectal cancer cells. In Cellular signalling, 88, 110148. doi:10.1016/j.cellsig.2021.110148. https://pubmed.ncbi.nlm.nih.gov/34530056/
8. Lei, Jun-Jie, Li, Hui-Qing, Mo, Zhi-Huai, Chen, Wen-Li, Zhang, Lei. 2019. Long noncoding RNA CDKN2B-AS1 interacts with transcription factor BCL11A to regulate progression of cerebral infarction through mediating MAP4K1 transcription. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 33, 7037-7048. doi:10.1096/fj.201802252R. https://pubmed.ncbi.nlm.nih.gov/30870006/
9. Chuang, Huai-Chia, Tan, Tse-Hua. 2019. MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus. In Cells, 8, . doi:10.3390/cells8111433. https://pubmed.ncbi.nlm.nih.gov/31766293/
10. Tomasoni, Mattia, Beyeler, Michael Johannes, Vela, Sofia Ortin, Bergin, Ciara, Bergmann, Sven. 2023. Genome-wide Association Studies of Retinal Vessel Tortuosity Identify Numerous Novel Loci Revealing Genes and Pathways Associated With Ocular and Cardiometabolic Diseases. In Ophthalmology science, 3, 100288. doi:10.1016/j.xops.2023.100288. https://pubmed.ncbi.nlm.nih.gov/37131961/