CSF-1 RESPONSIVE G1 CYCLINS IN HEMATOPOIETIC MALIGNANCY

集落刺激因子1（CSF-1）刺激细胞增殖， 支持单核细胞的分化和存活 吞噬细胞系 它的多效性作用是通过它的 与由c-CSF编码的单一类别的CSF-1受体（CSF-1 R）结合， fms原癌基因 配体激活的CSF-1 R酪氨酸激酶 磷酸化细胞质效应分子， 传递控制CSF-1应答基因转录的信号。 尽管CSF-1受体触发的信号诱导了一系列的 典型的“立即早期反应”基因（例如c-fos、junB、c-jun、c myc等）在生长因子刺激后1-2小时内， 在整个G1间期持续需要CSF-1 这表明，其他“延迟早期反应”基因的激活， 还需要确保进展到S期。 后一种基因 包括一个新D-型G1细胞周期蛋白家族，假设其 整合生长因子诱导的信号与细胞周期时钟， 从而通过一个或多个G1控制来调节时间转换 点 最近的证据表明，D型细胞周期蛋白的表达失调， 基因会导致肿瘤形成。 至少两种不同的D型细胞周期蛋白 基因是染色体易位、基因扩增和 逆转录病毒插入突变在多种肿瘤中，包括B 和T细胞淋巴瘤、甲状旁腺腺瘤，可能还有 胸部头部和颈部 我们已经克隆了人细胞周期蛋白D1，D2， D3基因定位于染色体11 q13、12 p13和6p 21， 并已开始筛选肿瘤材料和细胞系 从患有不同造血系统恶性肿瘤的患者中建立， 可能影响细胞周期蛋白D转录的染色体重排。 由于细胞周期蛋白通常作为细胞周期蛋白的调节亚基发挥作用， 依赖性激酶（CDK），我们试图确定CDK D型细胞周期蛋白的伴侣，并最终希望延长遗传 分析这些尚未确定的基因座。 我们也在探索 细胞周期蛋白D/cdk的作用可能是通过 它们与视网膜母细胞瘤基因产物（p105 Rb）的相互作用和/或 相关蛋白（Rb样p107蛋白），这反过来又被 参与负调节细胞周期进程。 主题 符合本项目的总体目标 赠款，但因为这项工作已通过一个独立的资助 机制，不要求直接支助。

Colony-stimulating factor 1 (CSF-1) stimulates the proliferation and supports the differentiation and survival of cells of the mononuclear phagocyte lineage. Its pleiotropic actions are mediated through its binding to a single class of CSF-1 receptors (CSF-1R) encoded by the c- fms proto-oncogene. The ligand-activated CSF-1R tyrosine kinase phosphorylates cytoplasmic effector molecules, which act in concert to relay signals that govern the transcription of CSF-1 responsive genes. Although signals triggered by the CSF-1 receptor induce a series of canonical "immediate early response" genes (e.g. c-fos, junB, c-jun, c- myc, etc.) within 1-2 hours following growth factor stimulation, the continued requirement for CSF-1 throughout the entire G1 interval suggests that the activation of other "delayed early response" genes is also required to ensure progression into S-phase. The latter genes include a novel family of D-type G1 cyclins that are hypothesized to integrate growth factor-induced signals with the cell cycle clock, thereby regulating temporal transitions through one or more G1 control points. Recent evidence suggests that deregulated expression of D-type cyclin genes can contribute to neoplasia. At least two distinct D-type cyclin genes are targets of chromosomal translocations, gene amplification, and retroviral insertional mutagenesis in a variety of tumors, including B and T cell lymphomas, parathyroid adenomas, and possibly, carcinomas of the breast, head, and neck. We have cloned the human cyclin D1, D2, and D3 genes, mapped them to chromosomes 11q13, 12p13, and 6p21, respectively, and have begun to screen tumor material and cell lines established from patients with different hematopoietic malignancies for chromosomal rearrangements that might affect cyclin D transcription. Because cyclins normally function as regulatory subunits of cyclin- dependent kinases (cdks), we are attempting to identify the cdk partner(s) of D-type cyclins and, ultimately, hope to extend the genetic analyses to these as yet unidentified loci. We are also exploring the possibility that the effects of cyclin D/cdk may be mediated through their interaction with the retinoblastoma gene product (p105Rb) and/or related proteins (the Rb-like p107 protein), which have in turn been implicated in negatively regulating cell cycle progression. The theme of this project conforms with the overall goals of this Program Project Grant, but because the work has been funded through an independent mechanism, no direct support is requested.