COORDINATE REGULATION BY MAP3K4 OF EPIGENETIC MODIFIERS CONTROLLING EMT

MAP3K4 对控制 EMT 的表观遗传修饰子的协调调控

• 批准号: 9892315
• 负责人: Amy N Abell
• 金额: $ 8.75万
• 依托单位: UNIVERSITY OF MEMPHIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9892315
• 关键词: Acetylation; Acetyltransferase; Actins; Active Sites; Adherence; Apical; Back; Biological; Biological Assay; Biological Markers; Biological Process; Breast Cancer Cell; Cancer Control; Cancer Patient; Cause of Death; Cell Surface Proteins; Cells; ChIP-seq; Characteristics; Chromatin Remodeling Factor; Cytoskeleton; Data; Deacetylase; Deacetylation; Decidual Cell Reactions; Defect; Development; Disease; Drug Targeting; Epigenetic Process; Epithelial; Epithelial Cells; Event; Fibrosis; GALNT3 gene; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Goals; HDAC6 gene; Histone Acetylation; Histone H2A; Histone H2B; Human; In Vitro; Individual; Inflammation; Injections; Kidney; Liver; Lung; Lysine; Malignant Neoplasms; Mediating; Mesenchymal; Molecular; Morphology; Mus; Mutation; Neoplasm Metastasis; Overlapping Genes; Pathologic; Pathology; Phenotype; Phosphotransferases; Physiological Processes; Process; Property; Proteins; Publishing; Regulation; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; System; Tissues; Work; base; blastocyst; cancer cell; cell motility; chromatin remodeling; conventional therapy; epigenetic regulation; epithelial to mesenchymal transition; human disease; in vivo; in vivo Model; inhibitor/antagonist; innovation; knock-down; malignant breast neoplasm; new therapeutic target; novel; novel strategies; overexpression; prevent; programs; promoter; small hairpin RNA; stemness; targeted treatment; therapy resistant; tissue regeneration; transcription factor; transcriptome sequencing; trophoblast

PROJECT SUMMARY Epithelial to mesenchymal transition (EMT) is a developmental program in which non-motile epithelial cells with tight cell-cell adherence convert into individual, motile mesenchymal cells. Importantly, EMT is reversible through a mesenchymal to epithelial transition (MET) converting mesenchymal cells back to an epithelial state. The EMT program is essential for normal processes during development and for tissue regeneration. EMT is reactivated in human diseases including tissue fibrosis in the kidney, liver, and lung and in cancer metastasis, making EMT a key target for drug therapy. Targeted mutation of the active site lysine of the kinase MAP3K4 in the mouse (KI4) results in severe developmental defects due to disrupted EMT. Epithelial trophoblast stem (TS) cells from kinase-inactive MAP3K4 (KI4) mice (TSKI4 cells) are uniquely paused in the intermediate stages of EMT, expressing both epithelial and mesenchymal characteristics while maintaining stemness. Induction of EMT in TSKI4 cells is due in part to the loss of MAP3K4/CBP mediated acetylation of histone H2B on the promoters of genes controlling the epithelial phenotype. We have recently discovered that loss of MAP3K4 activity increases the expression and activity of another chromatin remodeler, HDAC6. The goal of this project is to define the molecular network regulated by MAP3K4 controlling EMT. This network includes signaling pathways leading to the epigenetic regulation of genes important for EMT. Our approach is based on both our published work and new findings showing that MAP3K4 coordinates EMT by activating CBP and inhibiting HDAC6 on the promoters of genes important for EMT. We predict that genes in this MAP3K4 controlled network are critical to EMT-related pathologies. Our rationale is based on our findings of overlapping gene expression signatures between our TSKI4 stem cells and claudin low breast cancer cells that both display characteristics of stemness and EMT. Cancers with these characteristics frequently are both metastatic and display resistance to therapy. Protein networks that regulate the EMT transition represent potential targets for therapy with the rationale that reversal of EMT would restore sensitivity towards therapy. Our preliminary work using this innovative system has successfully identified new genes in breast cancer that control EMT/MET. Aim1 uses RNA-seq and ChIP-seq to identify a MAP3K4/CBP/HDAC6/H2BK5Ac dependent network that controls EMT. Aim 2 is a mechanistic study of the role of MAP3K4 and HDAC6 in EMT and the impact on the KI4 cellular and organismal phenotypes. The third aim targets GALNT3, a MAP3K4/CBP/HDAC6/H2BK5Ac co- regulated gene, defining the mechanisms by which GALNT3 controls EMT. Together, the three aims of this proposal will define the signaling mechanisms by which MAP3K4 coordinates the cellular phenotype through the co-regulation of the chromatin modifiers CBP and HDAC6. Further, this proposal will identify and characterize novel genes regulating epithelial/mesenchymal states, leading to the discovery of new biomarkers and drug targets for the identification and treatment of EMT related pathologies like fibrosis and metastasis.

项目摘要 上皮细胞向间质细胞转化（EMT）是一个发育过程，其中具有非运动性的上皮细胞， 紧密的细胞-细胞粘附转化成单个的、能动的间充质细胞。重要的是，EMT是可逆的 通过间充质到上皮转化（MET）将间充质细胞转化回上皮状态。 EMT程序对于发育期间的正常过程和组织再生至关重要。EMT是 在包括肾、肝和肺中的组织纤维化和癌症转移的人类疾病中重新活化， 使EMT成为药物治疗的关键目标。激酶MAP 3 K4活性位点赖氨酸的靶向突变 小鼠（KI 4）由于EMT被破坏而导致严重的发育缺陷。上皮滋养细胞干 (TS)来自激酶失活的MAP 3 K4（KI 4）小鼠的细胞（TSKI 4细胞）独特地暂停在中间阶段 EMT，表达上皮和间充质特征，同时保持干细胞。诱导 TSKI 4细胞中的EMT部分是由于MAP 3 K4/CBP介导的组蛋白H2 B乙酰化在TSKI 4细胞中的缺失。 控制上皮表型的基因的启动子。我们最近发现MAP 3 K4的缺失 活性增加了另一种染色质重塑剂HDAC 6的表达和活性。这个项目的目标 目的是明确MAP 3 K4调控EMT的分子网络。该网络包括信令 导致对EMT重要的基因的表观遗传调节的途径。我们的方法基于我们的 已发表的工作和新的发现表明，MAP 3 K4通过激活CBP和抑制EMT来协调EMT。 HDAC 6对EMT重要基因启动子的作用。我们预测MAP 3 K4中的基因控制着 网络对于EMT相关的病理至关重要。我们的理论基础是我们的发现重叠基因 我们的TSKI 4干细胞和claudin低乳腺癌细胞之间的表达特征， 干性和EMT的特征。具有这些特征的癌症通常是转移性的， 对治疗有抵抗力调节EMT转换的蛋白质网络代表了EMT的潜在靶点。 逆转EMT将恢复对治疗的敏感性。我们的前期工作 使用这种创新的系统已经成功地确定了乳腺癌中控制EMT/MET的新基因。 Aim 1使用RNA-seq和ChIP-seq鉴定MAP 3 K4/CBP/HDAC 6/H2 BK 5Ac依赖性网络， 控制急救人员。目的2是研究MAP 3 K4和HDAC 6在EMT中的作用以及对EMT的影响。 KI 4细胞和生物表型。第三个目标靶向GALNT 3，一个MAP 3 K4/CBP/HDAC 6/H2 BK 5Ac共- 调节基因，定义GALNT 3控制EMT的机制。这三个目标合在一起， 该提案将定义MAP 3 K4通过以下途径协调细胞表型的信号传导机制： 染色质修饰剂CBP和HDAC 6的共同调节。此外，该提案将确定并 表征调节上皮/间充质状态的新基因，从而发现新的生物标志物 以及用于鉴定和治疗EMT相关病理如纤维化和转移的药物靶标。

项目成果

MAP3K4 promotes fetal and placental growth by controlling the receptor tyrosine kinases IGF1R/IR and Akt signaling pathway.

MAP3K4通过控制受体酪氨酸激酶IGF1R/IR和AKT信号传导途径来促进胎儿和胎盘生长。

• DOI: 10.1016/j.jbc.2022.102310
• 发表时间: 2022-09
• 期刊: JOURNAL OF BIOLOGICAL CHEMISTRY
• 影响因子: 4.8
• 作者: Perry, Charles H.;Mullins, Nathan A.;Sweileh, Razan B. A.;Shendy, Noha A. M.;Roberto, Patrick A.;Broadhurst, Amber L.;Nelson, Hannah A.;Miranda-Carboni, Gustavo A.;Abell, Amy N.
• 通讯作者: Abell, Amy N.

MAP3K4 kinase activity dependent control of mouse gonadal sex determination†.

MAP3K4 激酶活性依赖性控制小鼠性腺性别决定。

• DOI: 10.1093/biolre/ioab083
• 发表时间: 2021
• 期刊: Biology of reproduction
• 影响因子: 3.6
• 作者: Shendy,NohaAM;Broadhurst,AmberL;Shoemaker,Kristin;Read,Robert;Abell,AmyN
• 通讯作者: Abell,AmyN

Controlling Epithelial to Mesenchymal Transition through Acetylation of Histone H2BK5.

通过组蛋白 H2BK5 的乙酰化控制上皮细胞向间质细胞的转变。

• 发表时间: 2017
• 期刊: Journal of nature and science
• 作者: Mobley,RobertJ;Abell,AmyN
• 通讯作者: Abell,AmyN

Coordinated regulation of Rel expression by MAP3K4, CBP, and HDAC6 controls phenotypic switching.

MAP3K4、CBP 和 HDAC6 对 Rel 表达的协调调节控制着表型转换。

• DOI: 10.1038/s42003-020-01200-z
• 发表时间: 2020
• 期刊: Communications biology
• 影响因子: 5.9
• 作者: Shendy,NohaAhmedMohammed;Raghu,Deepthi;Roy,Sujoy;Perry,CharlesHamilton;Safi,Adiba;Branco,MiguelRamos;Homayouni,Ramin;Abell,AmyNoel
• 通讯作者: Abell,AmyNoel

CYP1B1 Augments the Mesenchymal, Claudin-Low, and Chemoresistant Phenotypes of Triple-Negative Breast Cancer Cells.

• DOI: 10.3390/ijms23179670
• 发表时间: 2022-08-26
• 期刊: International journal of molecular sciences
• 影响因子: 5.6