NF-kB, CDK4 and JNK in Epidermal Growth Regulation

描述(由申请人提供)：程序性细胞死亡和增殖之间的精确平衡对于维持健康的自我更新表皮至关重要。这些过程中的异常是皮肤癌和一系列炎症性皮肤病的特征。核因子-kappaB/Rel蛋白是一个快速反应的转录因子家族，是表皮细胞生长的主要调节因子。最近的遗传学和生物化学研究证实，RelA核因子-kappaB亚单位是一种非冗余调节因子，通过下调CDK4和抑制JNK信号通路来触发表皮细胞生长停滞。与此相一致的是，在自发性人鳞状细胞癌(SCC)中检测到了核因子-KB的阻断以及JNK的激活和CDK4的上调。这些发现强调了CDK4和JNK在RERA调节表皮生长中的潜在重要性。然而，RERA抑制CDK4水平和JNK活性的机制尚不清楚，JNK级联反应在鳞癌等表皮异常生长疾病中的直接作用也尚未确定。 这项提案的第一个目标是确定调节RERA下调CDK4的机制。为了做到这一点，我们将调查我们最近发现的RelA和CDK4之间物理相互作用的性质和重要性。将进行系统的结构-功能研究，以确定参与CDK4调控和表皮细胞生长的relA结构域。T 他的第二个目标是确定JNK信号级联在与核因子-kappaB相关的表皮动态平衡和肿瘤形成中的作用。在有或没有抑制核因子-kappaB的情况下，将评估JNK途径功能的获得或丧失对CDK4水平和表皮生长的影响。JNK激活在促进肿瘤中的效力将通过基因干扰的方法在人类表皮组织中确定。 到这一资金阶段结束时，我们希望明确NF-kappaB、CDK4和JNK级联调控正常和肿瘤表皮组织生长的机制，并为未来针对皮肤癌等细胞异常生长疾病的分子靶点的开发提供洞察力。

DESCRIPTION (provided by applicant): A precise balance between programmed cell death and proliferation is essential to maintain a healthy self renewing epidermis. Abnormalities in these processes characterize skin cancer and a wide array of inflammatory skin diseases. NF-KappaB/Rel proteins, a family of rapidly responsive transcription factors, are major regulators of epidermal cell growth. Recent genetic and biochemical studies identified the RelA NF-kappaB subunit as a non-redundant regulator in triggering epidermal cell growth arrest through down regulation of CDK4 and suppression of JNK signaling. In agreement with these observations, NF-KB blockade along with JNK activation and CDK4 up-regulation was detected in spontaneous human squamous cell carcinoma (SCC). These findings underscore the potential importance of CDK4 and JNK in epidermal growth regulation by RelA. The mechanisms by which RelA suppresses CDK4 levels and JNK activity, however, are not clear and a direct role for JNK cascade in diseases of abnormal epidermal growth, such as SCC, has not been established. The first goal of this proposal is to define mechanisms mediating CDK4 down regulation by RelA. To do this, we will investigate the nature and importance of the physical interactions that we have recently identified between RelA and CDK4. Systematic structure-functional studies will be performed to identify RelA domains involved in CDK4 regulation and epidermal cell growth. T he second goal is to define the role of the JNK signaling cascade in epidermal homeostasis and neoplasia in relation to NF-KappaB. Effects of gain- or loss-of-function in the JNK pathway on CDK4 levels and epidermal growth with or without NF-KappaB inhibition will be assessed. The potency of JNK activation in tumor promotion will be defined in human epidermal tissue through genetic interference approaches. By the end of this funding period, we hope to have defined the mechanisms through which NF-kappaB, CDK4 and JNK cascade regulate growth of both normal and neoplastic epidermal tissue and to provide insight into development of future molecular targets for diseases of abnormal cell growth, such as skin cancers.