FUNCTION OF C-CAM IN PROSTATE CANCER

细胞粘附分子（CAM）在细胞凋亡中起着关键作用。 多细胞生物的发育和分化。 最近的研究表明，CAM基因或其 表达可能与癌症进展有关。 C-CAM是一个 上皮细胞CAM的IG超基因家族。 我们的研究表明， 在前列腺中，C-CAM主要在上皮细胞中表达， 其表达受雄激素调节。 下调或 在前列腺中观察到C-CAM表达完全丧失 上皮内瘤变（PIN）和前列腺癌，这表明， C-CAM可能是维持正常前列腺所必需的。 与这一观察相一致，我们证明了转染 的C-CAM 1到前列腺癌细胞系。 PC-3或DU 145 显著降低其致瘤性。相反，转染 将C-CAM 1反义基因导入非致瘤性NbE细胞 使其成为肿瘤。 这些结果表明，C-CAM 1 具有生长抑制作用。 基于这些结果，我们提出了研究机制， C-CAM 1通过其影响前列腺的生长和致瘤性 癌细胞 C-CAM 1可能抑制前列腺的致瘤性 因为C-CAM 1的表达激活了一种信号传导， 改变这些细胞的“分化状态”的途径， 从而干扰肿瘤细胞生长。 我们先前建议， 通过缺失描绘C-CAM中的肿瘤抑制结构域 分析. 我们已经实现了这一目标，并表明C- 细胞质末端结构域，而不是细胞外粘附 C-CAM 1的结构域在介导其肿瘤抑制作用中至关重要。 活动 我们还提出了鉴定和克隆细胞蛋白质 与C-CAM 1相互作用。 几个候选人相互作用 分子已被识别。 我们计划继续这项研究， 实现以下具体目标：1。以确定 C-CAM 1的胞质结构域是否足以 引发肿瘤抑制。 我们已经证明， C-CAM结构域是肿瘤抑制所必需的。 这个胞质结构域本身是否足以 活动尚不清楚。 我们将研究这一影响 胞质结构域（在不存在来自C- CAM 1）对相互作用蛋白质的影响。 几个候选C-CAM 1- 相互作用的蛋白质已经通过化学交联鉴定， 酵母双杂交和表达文库筛选方法。 我们 将进一步表征这些蛋白质， 评估其在C-CAM 1介导的生长中的作用的测定 镇压

Cell adhesion molecules (CAMs) play critical roles in the development and differentiation of multicellular organisms. Recent studies indicate that defects in CAM genes or in their expression may be related to cancer progression. C-CAM is an epithelial CAM of the Ig supergene family. Our studies show that in prostate C-CAM is mainly expressed in the epithelial cells and its expression is regulated by androgen. Down-regulation or complete loss of C-CAM expression was observed in prostate intraepithelial neoplasia (PIN) and prostate cancer, suggesting that C-CAM may be essential in maintinaing a normal prostate. Consistent with this observation, we demonstrated that transfection of C-CAM1 into the prostate cancer cell lines. PC-3 or DU145 markedly reduced their tumorigenicity. In contrast, transfection of a C-CAM1 antisense gene into a non-tumorigenic NbE cells rendered them tumorigenic. These results suggest that C-CAM1 has growth suppressive function. Based on these results, we propose to investigate the mechanims by which C-CAM1affects the growth and tumorigenicity of prostate cancer cells. C-CAM1 may suppress the tumorigenicity of prostate cancer cells because expression of C-CAM1 activates a signaling pathway that changes the "diferentiation state" of these cells and thus interferes with tumor cell growth. We previously proposed to delineate the tumor suppressor domain in C-CAM by deletion analysis. We have accomplished this goal and showed that the C- terminal cytoplasmic domain but ot the extracellular adhesion domain of C-CAM1 is critical in mediating its tumor-suppressive activity. We also proposed to identify and clone cellular proteins that interact with C-CAM1. Several candidate interacting molecules have been identified. We plan to continue this study by accomplishing the following Specific Aims: 1. To determine whether the cytoplasmic domain of C-CAM1 is sufficient for eliciting tumor suppression. We have shown that the cytoplasmic domain of C-CAM is required for the tumor suppression. Whether this cytoplasmic domain by itself is sufficient for this activity is not clear. We will examine the effects of this cytoplasmic domain (in the absence of other domains from C- CAM1) on interacting proteins. Several candidate C-CAM1- interacting proteins have been identified by chemical cross-linking, yeast two-hybrid, and expression library screening approaches. We will further characterize these proteins and perform functional assays to assess their roles in C-CAM1-mediated growth suppression.