Role of MIF in Rb inactivation and Tumorigenesis

MIF 在 Rb 失活和肿瘤发生中的作用

基本信息

批准号：
7909147
负责人：
ROBERT A MITCHELL
金额：
$ 11.96万
依托单位：
UNIVERSITY OF LOUISVILLE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909147
关键词：
Accounting Agar Binding Breast Cancer Cell Breast Carcinoma Cell Cycle Regulation Cell Line Cells Cyclin D1 Cyclin-Dependent Kinase 4 Cyclins Data Development Diagnostic Neoplasm Staging Disease Epidermal Growth Factor Epidermal Growth Factor Receptor Epithelial Cells Family Family member Fibroblasts Future Genetic Transcription Growth Growth Factor Growth Factor Receptors Guanosine Triphosphate Phosphohydrolases Human Human Mammary Carcinoma Immigration Inflammation Mediators Inflammatory Knowledge Laboratories Lead Link MCF7 cell Malignant - descriptor Malignant Epithelial Cell Malignant Neoplasms Mammary Neoplasms Mammary Tumorigenesis Mammary gland Mediating Mesenchymal Migration Inhibitory Factor Mitogen-Activated Protein Kinases Mitogens Mouse Mammary Tumor Virus Mus Mutation Nature Neoplasms Neoplastic Processes Normal Cell Oncogenes Oncogenic Pathologic Pathway interactions Phosphorylation Physiological Production Property Proto-Oncogenes Publishing RNA Interference Relative (related person)Resistance Retinoblastoma Role Signal Pathway Signal Transduction TP53 gene Testing Tumor Suppressor Proteins Tumor stage Viral Oncogene Work Xenograft procedure autocrine base breast tumorigenesis cancer cell cancer therapy cell growth cell motility cell transformation cytokine extracellular in vivo insight malignant breast neoplasm mouse model neoplastic neoplastic cell novel overexpression paracrine prognostic indicator receptor research study rho rho GTP-Binding Proteins therapeutic target tumor tumor growth tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Many human cancers require the production of soluble growth factors for tumor initiation, promotion and survival. These extracellular factors contribute to and promote most stages of tumor development. For example, tumors of the mammary gland are strongly influenced by the activity of epidermal growth factor (EGF) receptor family members. EGF binding to its cognate receptor is thought to contribute to breast cancer cell cycle regulation by activating signaling pathways that facilitate cyclin D1 expression, cyclin dependent kinase 4 or 6 (Cdk4t6) activation and, ultimately, retinoblastoma (Rb) inactivation. While Rb inactivation is critically important for oncogene-induced malignancies, the nature of the signals induced by oncogenes to facilitate this are incompletely understood. We recently discovered that the pro-inflammatory cytokine, migration inhibitory factor (MIF) is both necessary and sufficient for mitogen and oncogene-induced cyclin D1 transcription, Cdk4 activity and Rb inactivation. Moreover, our results reveal that MIF is strongly induced by tumor promoting oncogenes and cells from MIF-deficient mice are resistant to oncogene-induced malignant transformation. Despite these findings, more work is needed to investigate in detail the influence, mechanism and effectors of MIFs contribution to Rb inactivation, malignant growth properties and de novo tumorigenesis. We hypothesize that MIF promotes both normal and neoplastic cell growth by stimulating RhoA GTPase activity that leads to the activation of the canonical MAP kinase pathway and resulting in cyclin D1 transcription and Rb inactivation. To test the fundamentals of our hypothesis and fulfill the stated objectives of this application, the following specific aims are proposed: 1) Examine the regulatory and effector requirements for MIF in cyclin D1 transcription focusing on Rho GTPase activated pathways; 2) Test the requirements for MIF in human breast carcinoma Rho activation, cyclin D1 expression and Rb inactivation, and; 3) Investigate the contribution and functional requirements for MIF in de novo mammary tumorigenesis. This work should contribute to a greater understanding of the physiologic and pathologic importance of soluble growth factors to cell cycle regulation and neoplastic processes and may reveal a novel target for future cancer therapies.

描述（由申请人提供）：许多人类癌症需要产生可溶性生长因子来促进肿瘤的发生、促进和存活。这些细胞外因子有助于并促进肿瘤发展的大多数阶段。例如，乳腺肿瘤受表皮生长因子（EGF）受体家族成员活性的强烈影响。 EGF 与其同源受体结合被认为通过激活促进细胞周期蛋白 D1 表达、细胞周期蛋白依赖性激酶 4 或 6 (Cdk4t6) 激活以及最终视网膜母细胞瘤 (Rb) 失活的信号通路，从而有助于乳腺癌细胞周期调节。虽然 Rb 失活对于癌基因诱导的恶性肿瘤至关重要，但癌基因诱导的促进这一过程的信号的性质尚不完全清楚。我们最近发现促炎细胞因子迁移抑制因子 (MIF) 对于丝裂原和癌基因诱导的细胞周期蛋白 D1 转录、Cdk4 活性和 Rb 失活来说既是必要的也是充分的。此外，我们的结果表明，MIF 是由肿瘤促进癌基因强烈诱导的，并且来自 MIF 缺陷小鼠的细胞对癌基因诱导的恶性转化具有抵抗力。尽管有这些发现，仍需要更多的工作来详细研究 MIF 对 Rb 失活、恶性生长特性和从头肿瘤发生的影响、机制和效应物。我们假设 MIF 通过刺激 RhoA GTPase 活性来促进正常和肿瘤细胞生长，从而激活经典 MAP 激酶途径并导致细胞周期蛋白 D1 转录和 Rb 失活。为了测试我们假设的基础并实现本申请的既定目标，提出了以下具体目标：1）检查细胞周期蛋白 D1 转录中 MIF 的调节和效应器要求，重点关注 Rho GTPase 激活途径； 2) 测试人乳腺癌Rho激活、cyclin D1表达和Rb失活对MIF的要求； 3) 研究MIF在乳腺肿瘤新生发生中的贡献和功能需求。这项工作应有助于更好地了解可溶性生长因子对细胞周期调节和肿瘤过程的生理和病理重要性，并可能揭示未来癌症治疗的新靶点。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Amplification of tumor hypoxic responses by macrophage migration inhibitory factor-dependent hypoxia-inducible factor stabilization.

DOI：
10.1158/0008-5472.can-06-3292
发表时间：
2007
期刊：
Cancer research
影响因子：
11.2
作者：
Millicent Winner;A. Koong;B. Rendon;W. Zundel;R. Mitchell
通讯作者：
Millicent Winner;A. Koong;B. Rendon;W. Zundel;R. Mitchell

Stromal-dependent tumor promotion by MIF family members.

DOI：
10.1016/j.cellsig.2014.09.012
发表时间：
2014-12
期刊：
Cellular signalling
影响因子：
4.8
作者：
Mitchell RA;Yaddanapudi K
通讯作者：
Yaddanapudi K

MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation.

DOI：
10.1158/2326-6066.cir-15-0070-t
发表时间：
2016-02
期刊：
Cancer immunology research
影响因子：
10.1
作者：
Yaddanapudi K;Rendon BE;Lamont G;Kim EJ;Al Rayyan N;Richie J;Albeituni S;Waigel S;Wise A;Mitchell RA
通讯作者：
Mitchell RA

The MIF homologue D-dopachrome tautomerase promotes COX-2 expression through β-catenin-dependent and -independent mechanisms.