Role of MIF in Rb inactivation and Tumorigenesis

许多人类癌症需要产生可溶性生长因子，以启动、促进和促进肿瘤的发生 生死存亡。这些细胞外因子有助于并促进肿瘤发展的大部分阶段。为 例如，乳腺肿瘤受到表皮生长因子活性的强烈影响。 (EGF)受体家族成员。EGF与其同源受体结合被认为对乳房有贡献 通过激活促进细胞周期蛋白D1表达的信号通路来调节癌细胞周期。 依赖激酶4或6(CDK4t6)激活，最终导致视网膜母细胞瘤(RB)失活。而RB 失活对于癌基因诱导的恶性肿瘤是至关重要的，由 促进这一过程的致癌基因还不完全清楚。我们最近发现，促炎因子 细胞因子、迁移抑制因子(MIF)是丝裂原和癌基因诱导的充要条件 Cyclin D1转录、CDK4活性和Rb失活。此外，我们的结果表明，MIF具有很强的 促癌基因诱导和MIF基因缺陷小鼠细胞对癌基因诱导的抵抗 恶变。尽管有这些发现，但还需要更多的工作来详细调查这种影响， MIF在Rb失活、恶性生长和新生中的作用机制及影响因素 肿瘤发生学。我们假设MIF通过刺激细胞生长促进正常细胞和肿瘤细胞的生长 RhoA GTPase活性，导致规范的MAPK途径激活，并导致 Cyclin D1转录和Rb失活。测试我们假设的基本原理并实现所述的 本申请的目标，提出以下具体目标：1)审查监管和 Rho GTP酶激活途径对细胞周期蛋白D1转录中MIF效应的要求；2)测试 乳腺癌组织中MIF对Rho活化、细胞周期蛋白D1表达和Rb的要求 失活；3)研究MIF在新生乳腺中的作用和功能需求 肿瘤发生学。这项工作应该有助于更好地理解生理和病理。 可溶性生长因子对细胞周期调控和肿瘤过程的重要性，并可能揭示 未来癌症治疗的新靶点。

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.