Role of MIF in Rb inactivation and Tumorigenesis

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用于肿瘤的起始、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，乳腺肿瘤受到表皮生长因子（EGF）受体家族成员活性的强烈影响。EGF结合其同源受体被认为有助于乳腺癌细胞周期调节，通过激活信号通路，促进细胞周期蛋白D1的表达，细胞周期蛋白依赖性激酶4或6（Cdk 4 t6）的激活，并最终，视网膜母细胞瘤（Rb）失活。虽然Rb失活是癌基因诱导的恶性肿瘤至关重要的，由癌基因诱导的信号，以促进这是不完全理解的性质。我们最近发现，促炎细胞因子，迁移抑制因子（MIF）是必要的和足够的有丝分裂原和癌基因诱导的细胞周期蛋白D1转录，Cdk 4活性和Rb失活。此外，我们的研究结果表明，MIF是强烈诱导的肿瘤促进癌基因和细胞从MIF缺陷的小鼠是抵抗癌基因诱导的恶性转化。尽管有这些发现，还需要更多的工作来详细研究MIFs对Rb失活、恶性生长特性和新生肿瘤发生的影响、机制和效应物。我们推测，MIF促进正常和肿瘤细胞生长的刺激RhoA GT3活性，导致经典的MAP激酶途径的激活，导致细胞周期蛋白D1转录和Rb失活。为了检验我们的假设的基本原理并实现本申请所述的目的，提出了以下具体目标：1）检测MIF在细胞周期蛋白D1转录中的调节和效应子要求，重点是Rho GT3激活途径; 2）检测MIF在人乳腺癌Rho激活、细胞周期蛋白D1表达和Rb失活中的要求; 3）探讨MIF在乳腺肿瘤发生中的作用及功能需求。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控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。

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.