Role of MIF in Rb inactivation and Tumorigenesis

描述(申请人提供)：许多人类癌症需要产生可溶的生长因子，用于肿瘤的启动、促进和生存。这些细胞外因子有助于并促进肿瘤发展的大部分阶段。例如，乳腺肿瘤受到表皮生长因子(EGF)受体家族成员活性的强烈影响。与其同源受体结合的EGF被认为通过激活促进细胞周期蛋白D1表达的信号通路，促进细胞周期蛋白依赖的激酶4或6(CDK4t6)的激活，最终导致视网膜母细胞瘤(RB)失活，从而参与乳腺癌细胞周期的调节。虽然Rb失活对于癌基因诱导的恶性肿瘤是至关重要的，但癌基因诱导的促进这一过程的信号的性质还不完全清楚。我们最近发现，促炎症细胞因子迁移抑制因子(MIF)是有丝分裂原和癌基因诱导的细胞周期蛋白D1转录、CDK4活性和Rb失活的必要条件和充分条件。此外，我们的结果表明，MIF是由促肿瘤癌基因强烈诱导的，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，但还需要更多的工作来详细研究MIF在RB失活、恶性生长特性和新生肿瘤发生中的影响、机制和效应器。我们假设，MIF通过刺激RhoA GTPase活性促进正常和肿瘤细胞的生长，导致规范的MAP激酶途径的激活，并导致Cyclin D1转录和Rb失活。为了检验我们的假说的基本原理并实现本应用的既定目标，我们提出了以下具体目标：1)研究MIF在细胞周期蛋白D1转录中的调控和效应要求，重点是Rho GTP酶激活的途径；2)测试人乳腺癌中对MIF的要求；Rho激活、细胞周期蛋白D1表达和Rb失活；以及3)研究MIF在乳腺肿瘤发生中的作用和功能要求。这项工作有助于更好地理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，并可能为未来的癌症治疗提供一个新的靶点。

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.