Mechanism and Impact of an Interaction Between Keratin 19 and a Regulator of Gene Expression

角蛋白 19 与基因表达调节剂相互作用的机制和影响

• 批准号: 9440744
• 负责人: Byung Min Chung
• 金额: $ 47.31万
• 依托单位: CATHOLIC UNIVERSITY OF AMERICA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-07 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9440744
• 关键词: Address; Affect; Animal Model; Behavior; Binding; Biological Assay; Biological Markers; Breast Cancer Cell; Breast Cancer cell line; Breast cancer metastasis; CRISPR/Cas technology; Carcinoma; Cells; Clinical; Complex; Confocal Microscopy; Cytoplasm; Cytoskeletal Proteins; Cytoskeleton; Data; Defect; Development; Disease; Disease Progression; Expression Profiling; Family; Filament; Gene Expression; Genes; Genetic Transcription; Heterogeneous-Nuclear Ribonucleoprotein K; Human; In Vitro; Intermediate Filament Gene; Intermediate Filament Proteins; Intermediate Filaments; KRT19 gene; Keratin; Keratin-19; Knock-out; Knowledge; Lead; MDA MB 231; Malignant Neoplasms; Molecular; Monitor; Mutate; Mutation; Neoplasm Metastasis; PTGS2 gene; Pathway interactions; Patients; Phenotype; Phosphorylation; Phosphorylation Site; Phosphotransferases; Prognostic Marker; Protein Family; Proteins; Public Health; RNA; RNA-Binding Proteins; Regulation; Regulator Genes; Research; Resources; Ribonucleoproteins; Role; Skin; Skin Cancer; Specificity; Students; System; Technology; Testing; Tissues; Training; Treatment Efficacy; Tumor Markers; Work; base; c-myc Genes; cancer cell; cancer invasiveness; cell behavior; combat; dC-Stretch-Binding Protein; depolymerization; design; diagnostic biomarker; experimental study; human disease; in vivo; keratinocyte; malignant breast neoplasm; meetings; mutant; novel; novel therapeutics; nucleocytoplasmic transport; outcome forecast; overexpression; scaffold; tumor; tumor progression; tumorigenic

PROJECT SUMMARY Intermediate filament proteins make up the largest family of cytoskeletal proteins, and mutation or altered expression of intermediate filament proteins cause or significantly correlate with more than 80 human diseases. One key feature of the intermediate filament-associated diseases is altered expression profiles of genes that directly contribute to disease progression. One such disease type is epithelial cancers, where keratin intermediate filament proteins are widely used as diagnostic and prognostic markers for human patients, and select keratins promote tumor progression in animal models. In breast cancer, Keratin 19 (K19) is one of the most reliable and extensively studied diagnostic markers, and its higher expression correlates with worse patient prognosis. However, the specific impact of this biomarker in the tumor development remains unknown. Based on our preliminary data in human breast cancer cells and previous work on a related keratin in skin cancer cells, we propose that K19 regulates the expression of metastasis-related genes and promote metastatic cell behaviors through a direct interaction with hnRNP K. hnRNP K is a RNA-binding protein that regulates the expression of a host of pro-tumorigenic genes and promotes metastasis when accumulated in the cytoplasm. We hypothesize that K19 filaments function as cytoplasmic scaffolds for hnRNP K to post- transcriptionally regulate genes that promote invasive cell behaviors that lead to tumor metastasis. This proposal is aimed at uncovering the mechanistic details of how K19 and hnRNP K interact (Aim 1), and identifying the impact of K19-hnRNP K cooperation at the molecular and cellular levels, as well as the in vivo significance of their expression in tumor metastasis (Aim 2). Meeting the above aims will identify the contribution of a tumor marker towards metastasis, determine the regulatory mechanism governing expression of metastasis-associated genes, and reveal how the cytoplasmic accumulation of hnRNP K promotes metastasis. This proposal also has the potential to identify a novel regulator of intermediate filament organization. Ultimately, the knowledge gained can help develop novel therapeutic strategies to combat cancer and serve as a blueprint to better understand a myriad of diseases where intermediate filament genes are mutated or show altered expression.

项目概要 中间丝蛋白构成最大的细胞骨架蛋白家族，并且发生突变或改变 中间丝蛋白的表达导致 80 多种人类疾病或与 80 多种人类疾病显着相关。 中间丝相关疾病的一个关键特征是基因表达谱的改变，这些基因 直接促进疾病进展。其中一种疾病类型是上皮癌，其中角蛋白 中间丝蛋白被广泛用作人类患者的诊断和预后标记物，并且 选择角蛋白促进动物模型中的肿瘤进展。在乳腺癌中，角蛋白 19 (K19) 是其中之一 最可靠和广泛研究的诊断标记物，其较高的表达与较差的相关性 患者预后。然而，这种生物标志物对肿瘤发展的具体影响仍不清楚。 基于我们对人类乳腺癌细胞的初步数据以及之前对皮肤中相关角蛋白的研究 在癌细胞中，我们提出K19调节转移相关基因的表达并促进 通过与 hnRNP K 直接相互作用来控制转移细胞的行为。 hnRNP K 是一种 RNA 结合蛋白， 调节一系列促肿瘤基因的表达，并在累积时促进转移 细胞质。我们假设 K19 丝作为 hnRNP K 后的细胞质支架。 转录调节基因促进侵袭性细胞行为，从而导致肿瘤转移。这 该提案旨在揭示 K19 和 hnRNP K 如何相互作用的机制细节（目标 1），以及 确定 K19-hnRNP K 合作在分子和细胞水平以及体内的影响 它们的表达在肿瘤转移中的意义（目标 2）。实现上述目标将确定 肿瘤标志物对转移的贡献，确定控制表达的调节机制 转移相关基因，并揭示 hnRNP K 的细胞质积累如何促进 转移。该提案还有可能确定中间丝的新型调节剂 组织。最终，所获得的知识可以帮助开发新的治疗策略来对抗癌症 并作为更好地了解中间丝基因所在的多种疾病的蓝图 突变或表现出改变的表达。

项目成果

Tracking Single Cells Motility on Different Substrates.

• DOI: 10.3390/mps3030056
• 发表时间: 2020-08-04
• 期刊: Methods and protocols
• 影响因子: 2.4
• 作者: Sharma P;Lam VK;Raub CB;Chung BM
• 通讯作者: Chung BM

Keratin 19 maintains E-cadherin localization at the cell surface and stabilizes cell-cell adhesion of MCF7 cells.

• DOI: 10.1080/19336918.2020.1868694
• 发表时间: 2021-12
• 期刊: Cell adhesion & migration
• 影响因子: 3.2
• 作者: Alsharif S;Sharma P;Bursch K;Milliken R;Lam V;Fallatah A;Phan T;Collins M;Dohlman P;Tiufekchiev S;Nehmetallah G;Raub CB;Chung BM
• 通讯作者: Chung BM

Morphology, Motility, and Cytoskeletal Architecture of Breast Cancer Cells Depend on Keratin 19 and Substrate.

• DOI: 10.1002/cyto.a.24011
• 发表时间: 2020-11
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology
• 作者: Lam VK;Sharma P;Nguyen T;Nehmetallah G;Raub CB;Chung BM
• 通讯作者: Chung BM

Quantitative assessment of cancer cell morphology and motility using telecentric digital holographic microscopy and machine learning.

• DOI: 10.1002/cyto.a.23316
• 发表时间: 2018-03
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology
• 作者: Lam VK;Nguyen TC;Chung BM;Nehmetallah G;Raub CB
• 通讯作者: Raub CB