Role of MIF in Rb inactivation and Tumorigenesis

MIF 在 Rb 失活和肿瘤发生中的作用

• 批准号: 7097231
• 负责人: ROBERT A MITCHELL
• 金额: $ 23.54万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7097231
• 关键词: 3T3 cells; MCF7 cell; athymic mouse; breast neoplasms; cyclin dependent kinase; cyclins; enzyme activity; gene induction /repression; genetic transcription; genetically modified animals; guanine nucleotide binding protein; mammary epithelium; migration inhibition factor; mitogen activated protein kinase; molecular oncology; neoplastic cell; neoplastic growth; neoplastic transformation; protein structure function; retinoblastoma; tumor suppressor genes

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。