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 增殖导致癌症，而分化失败可导致不育。的细胞周期调节者与 TGF β超家族信号通路在这两个过程中起关键作用。细胞周期蛋白D2基因敲除的小鼠 颗粒细胞增殖和较小的睾丸，而p27基因敲除小鼠的支持细胞增殖增加 和颗粒细胞终末分化缺陷。在这笔赠款的支持下，我们已经表明， TGF β超家族的a：p成员，在性腺中作为肿瘤抑制因子发挥作用， D2/p27 性腺肿瘤非常迅速。促性腺激素（FSH和LH）也参与肿瘤发生 过程考虑到细胞周期蛋白D2、FSH和视网膜母细胞瘤（RB）肿瘤之间的新关系， 这与RB通路在大多数人卵巢中失调的发现一致， 我们的工作模型是RB是这些卵巢癌和睾丸癌发展的核心。 我们的总体假设是，BMPB/激活素/BMP、RB/E2 F、FSH、LH和细胞周期途径会聚 调节G1到S的相变和RB活性（磷酸化）状态的调节， 细胞周期调节剂（例如，细胞周期蛋白D2/CDK 4，细胞周期蛋白E2（E1）/CDK 2和p27）和细胞周期蛋白决定了 颗粒细胞或支持细胞的增殖和终末分化，最终影响 这些细胞的癌症。本研究的具体目的是：1）确定神经元的生理作用， 颗粒细胞和支持细胞增殖和分化中的视网膜母细胞瘤（RB）肿瘤抑制因子; 2） 确定RB蛋白质是否是在RMBin a敲除模型中肿瘤发展的遗传修饰剂; 3） 确定促黄体生成素（LH）和促卵泡激素（FSH）在颗粒细胞中的相对作用 细胞和支持细胞增殖、分化和肿瘤发展;以及4）表征改变 在细胞周期调节、细胞粘附和对LH的反应中， 颗粒细胞转化为癌症这些小鼠的特征将导致重要的见解， 男性和女性性腺癌的发展以及几种蛋白质在生殖系统中的作用 physiology.

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.