Studies on the Post-translational processing of MUC1

MUC1翻译后加工的研究

• 批准号: 8256635
• 负责人: Michael A. Hollingsworth
• 金额: $ 25.53万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8256635
• 关键词: Adenocarcinoma; Adhesions; Adhesives; Affect; Apical; Area; Autologous; Binding; Biological; Cell Adhesion Molecules; Cell Communication; Cell Nucleus; Cell Polarity; Cell physiology; Cell surface; Cells; Chromatin; Cleaved cell; Complex; Cytoplasmic Tail; Environment; Epithelial Cells; Estrogen Receptors; Event; Extracellular Domain; Extracellular Matrix; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Grant; Growth Factor; Health; Hepatocyte Growth Factor; Integrins; Interstitial Collagenase; Knowledge; Laboratories; Lateral; Lectin; Left; Ligands; Literature; MMP1 gene; Malignant Neoplasms; Mediator of activation protein; Modification; Molecular; Mucin-1 Staining Method; Mucins; Nature; Neoplasm Metastasis; Organ; Outcome; PDGFRA gene; Pancreas; Pancreatic Adenocarcinoma; Phosphorylation; Phosphotransferases; Play; Primary Neoplasm; Process; Property; Protein Tyrosine Kinase; Protein-Serine-Threonine Kinases; Proteins; Receptor Protein-Tyrosine Kinases; Role; Serine; Signal Transduction; Signal Transduction Pathway; Site; Structure; Surface; Surface Properties; Tandem Repeat Sequences; Threonine; Tissues; Transcription Factor AP-1; Transcriptional Regulation; Tumor Cell Invasion; Tyrosine; Work; beta catenin; cell motility; cell transformation; cytokine; extracellular; insight; meetings; metastatic process; neoplastic cell; overexpression; pancreatic neoplasm; platelet-derived growth factor BB; promoter; protein function; receptor; research study; residence; response; sensor; transcription factor; tumor

DESCRIPTION (provided by applicant): This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. Previous work has established that MUC1 is overexpressed and differentially glycosylated by different adenocarcinomas, and that this overexpression is associated with aggressive (invasive and metastatic) forms of pancreatic and other cancers. MUC1 plays multiple and key roles at the cell surface of epithelial cells: it configures some aspects of cell surface adhesion properties, and it communicates information about the status of the cell surface to the nucleus through participation in different pathways of signal transduction. We now know that alterations in MUC1 structure or binding status are communicated to internal compartments of the cell through modifications of the cytoplasmic tail, which can be phosphorylated by different serine, threonine and tyrosine kinases. Our recent results have revealed that MUC1 can have dramatic modulatory effects on cellular functions in response to external growth factor/cytokine stimulation through interactions with receptor tyrosine kinases. MUC1 overexpression on pancreatic tumor cells significantly increases the invasive and metastatic properties of cells stimulated with PDGF-BB. The mechanism whereby this occurs involves phosphorylation of the MUC1 cytoplasmic tail by PDGFR2 and subsequent signaling by the MUC1 cytoplasmic tail, which is transported to and modifies the transcriptional activity of specific promoter sites in the nucleus in association with other signaling and transcription factors. In contrast to the results with PDGF-BB, stimulation of pancreatic tumor cells with hepatocyte growth factor (HGF) under conditions of MUC1 overexpression decreases cell invasive through a mechanism in which MUC1 cytoplasmic tail phosphorylated by cMet associates with p53 and modulates the ability of p53 to associate with AP-1 at promoter sites and activate expression of genes associated with invasion (e.g. MMP1). These results support previous findings that MUC1 can influence the invasive and metastatic properties of tumors in different ways (both enhancing and decreasing). Our results provide a molecular explanation for these different effects by showing that they are context dependent and affected by the cytokine and tissue environment of the cell on which MUC1 is expressed. These results provide new insight into the overall metastatic process, in which cells first take on activities of invasion to leave a primary tumor site, which can be shut down when metastatic tumor cells take up residence in a new organ site and no longer need to migrate. As we go forward we have chosen to focus this renewal application on the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells. PUBLIC HEALTH RELEVANCE: This application proposes experiments that will further explore the molecular mechanisms by which the cell surface associated mucin, MUC1, contributes to the progression of pancreatic adenocarcinoma. This renewal application will investigate the mechanisms by which MUC1 is involved in signal transduction and transcriptional regulation, and how this influences invasion and metastasis of pancreatic tumor cells.

描述（由申请人提供）：本申请提出了进一步探索细胞表面相关粘蛋白 MUC1 促进胰腺腺癌进展的分子机制的实验。先前的工作已经确定，MUC1 在不同的腺癌中过度表达和差异糖基化，并且这种过度表达与胰腺癌和其他癌症的侵袭性（侵袭性和转移性）形式相关。 MUC1 在上皮细胞的细胞表面发挥着多种关键作用：它配置细胞表面粘附特性的某些方面，并通过参与不同的信号转导途径将有关细胞表面状态的信息传递给细胞核。我们现在知道，MUC1 结构或结合状态的改变是通过细胞质尾部的修饰传递到细胞内部区室的，细胞质尾部可以被不同的丝氨酸、苏氨酸和酪氨酸激酶磷酸化。我们最近的结果表明，MUC1 通过与受体酪氨酸激酶相互作用，可以响应外部生长因子/细胞因子刺激，对细胞功能产生显着的调节作用。胰腺肿瘤细胞上的 MUC1 过表达显着增加了 PDGF-BB 刺激的细胞的侵袭和转移特性。发生这种情况的机制涉及 MUC1 胞质尾部被 PDGFR2 磷酸化以及随后 MUC1 胞质尾部发出的信号，该信号被转运到细胞核中特定启动子位点并与其他信号和转录因子相关联，修改其转录活性。与 PDGF-BB 的结果相反，在 MUC1 过表达的条件下用肝细胞生长因子 (HGF) 刺激胰腺肿瘤细胞，通过 cMet 磷酸化的 MUC1 胞质尾部与 p53 结合并调节 p53 的能力的机制减少细胞侵袭。在启动子位点与 AP-1 结合并激活与入侵相关的基因（例如 MMP1）的表达。这些结果支持了之前的发现，即 MUC1 可以以不同方式（增强和减弱）影响肿瘤的侵袭和转移特性。我们的结果为这些不同的效应提供了分子解释，表明它们是环境依赖性的，并受到表达 MUC1 的细胞的细胞因子和组织环境的影响。这些结果为整个转移过程提供了新的见解，在这个过程中，细胞首先进行侵袭活动以离开原发肿瘤部位，当转移性肿瘤细胞在新的器官部位定居并且不再需要迁移时，这种侵袭活动可以被关闭。 。随着我们的前进，我们选择将这一更新应用的重点放在MUC1参与信号转导和转录调控的机制，以及它如何影响胰腺肿瘤细胞的侵袭和转移。公共健康相关性：本申请提出的实验将进一步探索细胞表面相关粘蛋白 MUC1 促进胰腺腺癌进展的分子机制。这项更新申请将研究MUC1参与信号转导和转录调控的机制，以及它如何影响胰腺肿瘤细胞的侵袭和转移。

项目成果

CFTR expression does not influence glycosylation of an epitope-tagged MUC1 mucin in colon carcinoma cell lines.

CFTR 表达不影响结肠癌细胞系中表位标记的 MUC1 粘蛋白的糖基化。

• 发表时间: 1999-04
• 影响因子: 4.3
• 作者: Reid, C J;Burdick, M D;Hollingsworth, M A;Harris, A
• 通讯作者: Harris, A

MicroRNA-200c modulates the expression of MUC4 and MUC16 by directly targeting their coding sequences in human pancreatic cancer.

MicroRNA-200c 通过直接靶向人类胰腺癌中的编码序列来调节 MUC4 和 MUC16 的表达。

• 发表时间: 2013
• 影响因子: 3.7
• 作者: Radhakrishnan, Prakash;Mohr, Ashley M;Grandgenett, Paul M;Steele, Maria M;Batra, Surinder K;Hollingsworth, Michael A
• 通讯作者: Hollingsworth, Michael A

Potential for H-DNA in the human MUC1 mucin gene promoter.

人类 MUC1 粘蛋白基因启动子中 H-DNA 的潜力。

• 发表时间: 1996-07-26
• 作者: Nelson, K L;Becker, N A;Pahwa, G S;Hollingsworth, M A;Maher 3rd, L J
• 通讯作者: Maher 3rd, L J

Microfluidic immunocapture of circulating pancreatic cells using parallel EpCAM and MUC1 capture: characterization, optimization and downstream analysis.

使用并行 EpCAM 和 MUC1 捕获对循环胰腺细胞进行微流体免疫捕获：表征、优化和下游分析。

• DOI: 10.1039/c4lc00041b
• 发表时间: 2014-04-14
• 期刊: Lab on a chip
• 影响因子: 6.1
• 作者: Fredrik I. Thege;Timothy Lannin;Trisha N. Saha;Shannon Tsai;M. Kochman;M. Hollingsworth;A. Rhim;B. Kirby
• 通讯作者: B. Kirby

P-selectin expression in a metastatic pancreatic tumor cell line (SUIT-2).

P-选择素在转移性胰腺肿瘤细胞系 (SUIT-2) 中的表达。

• DOI: 10.1016/j.ultsonch.2017.12.030
• 发表时间: 1997-03-15
• 期刊: Cancer research
• 影响因子: 11.2
• 作者: T. Iwamura;T. Caffrey;N. Kitamura;H. Yamanari;T. Setoguchi;M. Hollingsworth
• 通讯作者: M. Hollingsworth