Mechanisms of cell contact inhibition and their dysregulation in cancer.

描述（由申请人提供）：正常细胞在条件不适当时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，各种刺激如“细胞-细胞接触”会触发这些调节机制。这种“接触抑制”在肿瘤发生过程中经常变得失调，我们的长期目标是确定和描述细胞接触如何触发抗增殖/生长控制信号的机制。在这些信号的调控中起核心作用的是Merlin，它是NF2（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，NF2等位基因在广泛的肿瘤中功能失活。Merlin定位于细胞-细胞接触区域，其功能丧失的一个主要表现是体内肿瘤的发展和细胞增殖“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/Yap途径调节的信号转导途径。虽然这些通路在细胞增殖调节、器官大小控制和组织修复中发挥关键作用，但目前尚不清楚这些通路中哪一条介导了Merlin的肿瘤抑制功能。我们最近确定了血管运动蛋白家族的成员血管运动蛋白，作为梅林相互作用蛋白，定位于紧密和粘附的连接。重要的是，我们确定了Merlin调节有丝分裂信号的能力是通过血管平滑素介导的，并且血管平滑素是NF2动物模型中肿瘤发生所必需的。我们的工作假设是，Merlin作为肿瘤抑制因子，通过与血管运动素相互作用来调节控制细胞增殖的信号通路，并且靶向血管运动素可以抑制肿瘤发生。我们将使用基于细胞和动物的NF2模型来验证这些假设，以确定Merlin和血管运动素依赖的细胞增殖调节的机制，确定Hpo/Yap通路和血管运动素在NF2中的作用，并确定血管运动素是否可以在体内驱动肿瘤发生。考虑到NF2突变在多种癌症中的参与，这些研究将具有广泛的影响：1)阐明细胞与细胞接触调控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/YAP通路的作用；4)验证Angiomotins作为开发治疗干预措施的新靶点。

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.