Mechanisms of cell contact inhibition and their dysregulation in cancer.

描述（由申请人提供）：当条件不合适时，正常细胞具有抑制增殖的机制，而肿瘤细胞绕过这些机制并继续增殖。当细胞达到临界数量和密度时，这些调节机制由诸如“细胞-细胞接触”的不同刺激触发。这种“接触-抑制”在肿瘤发生期间经常变得失调，并且我们的长期目标是鉴定和表征细胞：细胞接触如何触发抗增殖/生长控制信号的机制。在这些信号的调节中的一个中心参与者是Merlin，NF 2（2型神经纤维瘤病）肿瘤抑制基因的蛋白产物。最近的研究表明，NF 2等位基因在广泛的肿瘤中功能失活。Merlin定位于细胞-细胞接触的区域，Merlin功能丧失的主要表现是体内肿瘤的发展和细胞增殖的“接触抑制”的丧失。Merlin已被证明是多种信号转导途径的关键调节剂，包括由小G蛋白和Hpo/雅普途径调节的信号转导途径。虽然这些途径在调节细胞增殖、器官大小控制和组织修复中发挥关键作用，但仍不清楚这些途径中的哪一种介导Merlin的肿瘤抑制功能。 我们最近确定了血管动素，运动蛋白家族的成员，作为梅林相互作用的蛋白质，定位于紧密连接和粘附连接。重要的是，我们确定Merlin调节促有丝分裂信号传导的能力是通过血管生成素介导的，并且血管生成素是NF 2动物模型中肿瘤发生所需的。我们的工作假设是，Merlin通过调节信号传导途径发挥肿瘤抑制剂的作用，所述信号传导途径通过与血管生成素相互作用来控制细胞增殖，并且靶向血管生成素将导致肿瘤发生的抑制。 我们将使用基于细胞的NF 2和动物模型来验证这些假设，以确定Merlin和血管动素依赖性调节细胞增殖的机制，建立Hpo/雅普通路和血管动素在NF 2中的作用，并确定血管动素是否可以驱动体内肿瘤发生。鉴于NF 2突变参与了广泛的癌症，这些研究将产生广泛的影响，并1）阐明通过细胞：细胞接触调节细胞增殖的分子机制，2）确定Merlin与肿瘤抑制相关的功能，3）确定Hpo/雅普途径的作用，4）验证血管生成素作为开发治疗干预的新靶点。

DESCRIPTION (provided by applicant): While normal cells possess mechanisms that inhibit proliferation when conditions are inappropriate, tumor cells circumvent these mechanisms and continue proliferating. These regulatory mechanisms are triggered by diverse stimuli such as "cell-cell contact", when cells reach a critical number and density. This "contact- inhibition" oftn becomes dysregulated during tumorigenesis and our long-term goals are to identify and characterize the mechanisms of how cell:cell contact triggers anti-proliferative/growth control signals. A central player in the regulation of these signals is Merlin, the protein product of the NF2 (neurofibromatosis type 2) tumor suppressor gene. Recent studies have indicated the NF2 allele is functionally inactivated in a broad range of tumors. Merlin is localized to regions of cel-cell contacts and a major manifestation of Merlin's loss of function is the development of tumors in vivo and loss of "contact inhibition" of cell proliferation. Merlin has been shown to function a a key regulator of multiple signal transduction pathways including those regulated by small G-proteins and the Hpo/Yap pathway. While these pathways play critical roles in regulation of cell proliferation, organ size control and tissue repair, it is still not clear which of these pathways mediates Merlin's tumor suppressive function/s. We recently identified the Angiomotins, members of the Motin protein family, as Merlin-interacting proteins that localize to tight and adherens junctions. Importantly, we determined that Merlin's ability to regulate mitogenic signaling is mediated through the Angiomotins and that the Angiomotins are required for tumorigenesis in an animal model of NF2. Our working hypotheses are that Merlin functions as a tumor suppressor by regulating signaling pathways that control cellular proliferation through interaction with the Angiomotins and that targeting the Angiomotins will result in inhibition of tumorigenesis. We will test these hypotheses employing cell-based and animal models of NF2 to identify the mechanisms underlying Merlin and Angiomotin-dependent regulation of cell proliferation, establish the roles of the Hpo/Yap pathway and Angiomotin in NF2 and determine whether Angiomotins can drive tumorigenesis in vivo. Given the involvement of NF2 mutations in a broad spectrum of cancers, these studies will have broad impact and 1) elucidate the molecular mechanisms underlying regulation of cellular proliferation by cell:cell contact, 2) determine the functions of Merlin relevant to tumor suppression, 3) establish a role for the Hpo/YAP pathway and 4) validate the Angiomotins as novel targets for development of therapeutic interventions.