Mouse Models to Study Gonadal Tumor Development

增殖和分化是卵巢和睾丸内的重要过程。不受控制 增殖会导致癌症，而分化失败则会导致不孕。细胞周期调节剂和 TGF(3超家族信号通路在这两个过程中都发挥着关键作用。Cyclin D2缺失小鼠的细胞减少 颗粒细胞增殖和睾丸变小，而 p27 缺失小鼠则支持细胞增殖增加 和颗粒细胞终末分化缺陷。在这笔赠款的支持下，我们已经证明 抑制素是 TGFp 超家族的 a:p 成员，在性腺中发挥肿瘤抑制因子的作用，并且细胞周期蛋白 D2/抑制素 a 双突变体减缓了肿瘤的发展，而 p27/抑制素 a 双突变体则死于肿瘤 性腺肿瘤的发生非常迅速。两种促性腺激素（FSH 和 LH）也参与肿瘤发生 过程。鉴于细胞周期蛋白 D2、FSH 和视网膜母细胞瘤 (RB) 肿瘤之间的新关系 颗粒细胞中的抑制因子，与大多数人类中 RB 途径失调的发现一致 对于癌症，我们的工作模型是 RB 对这些卵巢癌和睾丸癌的发展至关重要。 我们的总体假设是抑制素/激活素/BMP、RB/E2F、FSH、LH 和细胞周期途径会聚 调节 G1 到 S 相变以及 RB 活性（磷酸化）状态的调节 细胞周期调节因子（例如细胞周期蛋白 D2/CDK4、细胞周期蛋白 E2(E1)/CDK2 和 p27）和抑制素决定 颗粒细胞或支持细胞的增殖和终末分化，最终影响 这些细胞会导致癌症。拟议研究的具体目标是： 1）定义 视网膜母细胞瘤 (RB) 颗粒细胞和支持细胞增殖和分化的肿瘤抑制因子； 2） 确定RB蛋白是否是抑制素敲除模型中肿瘤发展的遗传修饰剂； 3） 确定黄体生成素 (LH) 和卵泡刺激素 (FSH) 在颗粒中的相对作用 细胞和支持细胞增殖、分化和肿瘤发展； 4) 描述变化的特征 在转化早期发生的细胞周期调节、细胞粘附和对 LH 的反应中 颗粒细胞转变为癌症。这些小鼠的表征将带来对这些小鼠的重要见解 男性和女性性腺癌的发生以及几种蛋白质在生殖中的作用 生理学。

Proliferation and differentiation are important processes within the ovaries and testes. Uncontrolled proliferation results in cancer whereas failure to differentiate can result in infertility. Cell cycle regulators and TGF(3 superfamily signaling pathways play key roles in both processes. Cyclin D2 null mice have decreased granulosa cell proliferation and smaller testes whereas p27 null mice have increased Sertoli cell proliferation and defects in granulosa cell terminal differentiation. With the support of this grant, we have shown that the inhibins, a:p members of the TGFp superfamily, function in the gonads as tumor suppressors and that cyclin D2/inhibin a double mutants have slowed tumor development whereas p27/inhibin a double mutants die of gonadal tumors very rapidly. Both gonadotropins (FSH and LH) are also involved in the tumorigenesis process. Given the emerging relationship between cyclin D2, FSH, and the retinoblastoma (RB) tumor suppressor in granulosa cells and consistent with findings that the RB pathway is deregulated in most human cancers, our working model is that RB is central to the development of these ovarian and testicular cancers. Our overall hypothesis is that the inhibin/activin/BMP, RB/E2F, FSH, LH, and cell cycle pathways converge to regulate the G1 to S phase transition and that modulation of the activity (phosphorylation) state of RB by cell cycle regulators (e.g., cyclin D2/CDK4, cyclin E2(E1)/CDK2, and p27) and inhibin determines the proliferation and terminal differentiation of granulosa or Sertoli cells, ultimately affecting the predisposition of these cells to cancer. The Specific Aims of the proposed studies are: 1) Define the physiologic roles of the retinoblastoma (RB) tumor suppressor in granulosa cell and Sertoli cell proliferation and differentiation; 2) Determine if the RB protein is a genetic modifier of tumor development in the inhibin a knockout model; 3) Establish the relative roles of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in granulosa cell and Sertoli cell proliferation, differentiation, and tumor development; and 4) Characterize the alterations in cell cycle regulation, cell adhesion, and responsiveness to LH that occur early in the transformation of granulosa cells into cancer. Characterization of these mice will lead to important insights into the development of gonadal cancers in men and women and the roles of several proteins in reproductive physiology.