Role of Cten in Prostate Cancer

描述（由申请人提供）：前列腺癌是北美男性最常见的恶性肿瘤。然而，与前列腺细胞恶性转化相关的遗传事件在很大程度上是未知的。新的前列腺特异性基因的鉴定可以提供新的标记物，并有助于开发新的治疗方式。张力素是一种与肌动蛋白细胞骨架相互作用并介导信号转导的黏附分子。在分离紧张素家族基因的过程中，我们发现了一个新的c端类似紧张素的分子，cten。Cten是一个715个氨基酸的分子，含有src同源性2和与张力蛋白相似的磷酸酪氨酸结合域。然而，cten不具有张力蛋白家族中发现的肌动蛋白结合活性，并且分子质量要小得多。有趣的是，cten的表达仅限于前列腺和胎盘，并且在前列腺癌/细胞系中经常减少/缺失。此外，人类cten基因位于染色体17q21上，这一区域在前列腺癌中经常被删除。Cten局限于局灶粘连，但与张力蛋白不同，它也存在于细胞核中。我们假设cten是一种前列腺特异性肿瘤抑制因子，在局灶粘连和细胞核之间的信号传导中起重要作用；而cten表达或功能的改变破坏了它的正常活动，增加了患前列腺癌的风险。本提案的总体目标是确定cten的表达是否可用于疾病进展的早期发现、诊断和监测，并研究cten在前列腺癌中的功能。

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy in North American men. However, the genetic events associated with the malignant transformation of prostatic cells are largely unknown. Identification of new prostate specific genes could provide new markers and could be instrumental for development of new treatment modalities. Tensin is a focal adhesion molecule that interacts with the actin cytoskeleton and mediates signal transduction. During the course of isolating tensin family genes, we have identified a novel C-terminal tensin-like molecule, cten. Cten is a 715 amino acid molecule containing src homology 2 and phosphotyrosine-binding domains that are similar to tensins. However, cten does not have the actin-binding activities found in tensin family and is much smaller in molecular mass. Interestingly, the expression of cten is restricted to prostate and placenta, and is often reduced/lost in prostate cancer/cell lines. In addition, human cten gene is located on chromosome 17q21, a region often deleted in prostate cancer. Cten localizes to focal adhesions, but unlike tensins, it is also found in nucleus. We hypothesize that cten is a prostate-specific tumor suppressor that plays an important role in signaling between focal adhesions and the nucleus; and that alteration of cten expression or function disrupts its normal actions and increases the risk for prostate cancer. The overall goal of this proposal is to determine whether the expression of cten can be used in early detection, diagnosis and monitoring of disease progression, and to study the function of cten in prostate cancer. There are three specific aims: Aim 1. To establish the value of cten expression patterns in prostate cancer diagnosis and prognosis. Aim 2. To determine the role of cten on the phenotype of prostate cancer cells, and elucidate the functions of its subcellular localization, using in vitro model systems. Aim 3. To determine the function of cten in prostate physiology and carcinogenesis, using in vivo models of transgenic mice expressing wild-type or mutated human cten.