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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >p300 Acetyltransferase Is a Cytoplasm‐to‐Nucleus Shuttle for SMAD2/3 and TAZ Nuclear Transport in Transforming Growth Factor β–Stimulated Hepatic Stellate Cells
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p300 Acetyltransferase Is a Cytoplasm‐to‐Nucleus Shuttle for SMAD2/3 and TAZ Nuclear Transport in Transforming Growth Factor β–Stimulated Hepatic Stellate Cells

机译：P300乙酰转移酶是用于SMAD2 / 3的细胞质 - 到核梭，以及转化生长因子β刺激的肝星状细胞的TAZ核传输

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摘要

Nuclear translocation of mothers against decapentaplegic homolog 2/3 (SMAD2/3), core transcription factors of transforming growth factor β (TGF‐β) signaling, is critical for hepatic stellate cell (HSC) differentiation into metastasis‐promoting myofibroblasts. SMAD2/3 have multiple coactivators, including WW domain‐containing transcription regulator protein 1 (WWTR1 or TAZ) and p300 acetyltransferase. In the nucleus, TAZ binds to SMAD2/3 to prevent SMAD2/3 nuclear export. However, how TAZ and SMAD2/3 enter the nucleus remains poorly understood because neither contains a nuclear localization signal (NLS), an?amino acid?sequence tagging proteins for?nuclear transport. p300 is an NLS‐containing large scaffold protein, so we hypothesized that SMAD2/3 and TAZ may undergo nuclear import through complexing with p300. Coimmunoprecipitation, immunofluorescence, and nuclear fractionation assays revealed that TGF‐β1 promoted binding of SMAD2/3 and TAZ to p300 and that p300 inactivation disrupted TGF‐β1‐mediated SMAD2/3 and TAZ nuclear accumulation. Deleting the p300 NLS blocked TGF‐β1‐induced SMAD2/3 and TAZ nuclear transport. Consistently, p300 inactivation suppressed TGF‐β1‐mediated HSC activation and transcription of genes encoding tumor‐promoting factors, such as connective tissue growth factor, Tenascin C, Periostin, platelet‐derived growth factor C, and fibroblast growth factor 2, as revealed by microarray analysis. Chromatin immunoprecipitation‐real‐time quantitative PCR showed that canonical p300‐mediated acetylation of histones also facilitated transcription in response to TGF‐β1 stimulation. Interestingly, although both TGF‐β1‐mediated and stiffness‐mediated HSC activation require p300, comparison of gene expression data sets revealed that transcriptional targets of TGF‐β1 were distinct from those of stiffness‐p300 mechanosignaling. Lastly, in tumor/HSC coinjection and intrasplenic tumor injection models, targeting p300 of activated‐HSC/myofibroblasts by C646, short hairpin RNA, or cre ‐mediated gene disruption reduced tumor and liver metastatic growth in mice. Conclusion: p300 facilitates TGF‐β1‐stimulated HSC activation by both noncanonical (cytoplasm‐to‐nucleus shuttle for SMAD2/3 and TAZ) and canonical (histone acetylation) mechanisms. p300 is an attractive target for inhibiting HSC activation and the prometastatic liver microenvironment.
机译：母亲对decapentaplegic同源物2/3（SMAD2 / 3），转化生长因子β（TGF-β）的信令的核心转录因子的核转位，是肝星状细胞（HSC）分化成转移促进成肌纤维细胞的关键。 Smad2 / 3的具有多个辅激活物，包括含有WW结构域的转录调节蛋白1（WWTR1或TAZ）和p300乙酰转移酶。在细胞核中，TAZ结合到SMAD2 / 3，以防止SMAD2 / 3核出口。然而，TAZ和SMAD2 / 3如何进入细胞核仍然知之甚少因为既不包含核定位信号（NLS），α-氨基酸？序列标记蛋白为？核运输。 P300是一种含有NLS-大支架蛋白，所以我们推测，SMAD2 / 3和TAZ可以通过与P300络合进行核进口。免疫共沉淀，免疫荧光和核分馏实验表明，TGF-β1升职SMAD2 / 3和TAZ对P300绑定和P300灭活扰乱TGF-β1介导的SMAD2 / 3和TAZ核积累。删除P300 NLS阻断TGF-β1诱导SMAD2 / 3和TAZ核运输。一致地，P300失活抑制TGF-β1介导的HSC活化和编码肿瘤促进因素，如结缔组织生长因子基因的转录，生腱蛋白C，骨膜素，血小板衍生的生长因子C，和成纤维细胞生长因子2，如通过显示微阵列分析。染色质免疫沉淀实时定量PCR结果显示组蛋白是规范P300介导的乙酰化也促进转录响应TGF-β1刺激。有趣的是，尽管这两个TGF-β1介导的和刚性介导的HSC活化需要P300，基因表达数据集的比较揭示TGF-β1的那转录目标是从那些刚度-P300 mechanosignaling的不同。最后，在肿瘤/ HSC共注射和脾内注射肿瘤模型中，靶向激活-HSC的P300 /由C646，短发夹RNA，肌成纤维细胞或CRE介导的基因破坏降低了肿瘤和肝脏转移性生长在小鼠。结论：P300促进TGF-β1刺激的HSC活化双方非规范（细胞质至细胞核穿梭为SMAD2 / 3和TAZ）和经典的（组蛋白乙酰化）的机制。 P300是用于抑制HSC活化和前转移肝脏微环境有吸引力的目标。

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  • 作者

    Wang Yuanguo; Tu Kangsheng; Liu Donglian; Guo Luyang; Chen Yunru; Li Qing; Maiers Jessica L.; Liu Zhikui; Shah Vijay H.; Dou Changwei; Tschumperlin Daniel; Voneschen Luke; Yang Rendong; Kang Ningling;

  • 作者单位

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

    GI Research Unit and Cancer Cell Biology ProgramMayo ClinicRochester MN;

    1st Affiliated Hospital of Xi'an Jiaotong UniversityXi'an Shanxi P. R. China;

    GI Research Unit and Cancer Cell Biology ProgramMayo ClinicRochester MN;

    GI Research Unit and Cancer Cell Biology ProgramMayo ClinicRochester MN;

    Department of Physiology and Biomedical EngineeringMayo ClinicRochester MN;

    Computational Cancer GenomicsHormel Institute University of MinnesotaAustin MN;

    Computational Cancer GenomicsHormel Institute University of MinnesotaAustin MN;

    Tumor Microenvironment and MetastasisHormel Institute University of MinnesotaAustin MN;

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  • 中图分类 消化系及腹部疾病;
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