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，而不分化可能会导致不孕。细胞周期调节因子和 转化生长因子(3)超家族信号通路在这两个过程中都起着关键作用。细胞周期蛋白D2缺失的小鼠数量减少 颗粒细胞增殖和较小的睾丸，而p27基因缺失的小鼠增加了支持细胞的增殖 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，在性腺中作为肿瘤抑制因子发挥作用，并在细胞周期中发挥作用。 D2/抑制素a双突变延缓了肿瘤的发展，而p27/抑制素a双突变则死于 性腺肿瘤非常迅速。促性腺激素(卵泡刺激素和促黄体生成素)也参与肿瘤的发生。 进程。鉴于细胞周期蛋白D2、卵泡刺激素与视网膜母细胞瘤(RB)肿瘤的关系 颗粒细胞中的抑制子，并与大多数人类中Rb途径被解除调控的发现一致 对于癌症，我们的工作模型是RB在这些卵巢癌和睾丸癌的发展中处于中心地位。 我们的总体假设是抑制素/激活素/骨形态发生蛋白、Rb/E2F、FSH、黄体生成素和细胞周期通路趋同 调节G1期向S相变和Rb活性(磷酸化)状态的调节 细胞周期调节因子(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 这些细胞转化为癌症。拟议研究的具体目的是：1)确定 视网膜母细胞瘤(RB)抑制颗粒细胞和支持细胞的增殖和分化；2) 在抑制素基因敲除模型中确定Rb蛋白是否是肿瘤发生的遗传修饰物；3) 黄体生成素和卵泡刺激素在颗粒细胞中的相对作用 细胞和支持细胞的增殖、分化和肿瘤的发展；以及4)改变的特征 在细胞周期调节、细胞黏附和对促黄体生成素的反应中，发生在转化的早期 颗粒细胞转化为癌细胞。对这些小鼠的表征将导致对 性腺癌在男性和女性中的发展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.