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。在这些过程中，皮肤癌和一系列炎症性皮肤病的特征是明显的。NF-κ B/Rel蛋白是一个快速响应的转录因子家族，是表皮细胞生长的主要调节因子。最近的遗传和生物化学研究确定RelA NF-κ B亚基作为非冗余调节剂，通过下调CDK 4和抑制JNK信号传导触发表皮细胞生长停滞。与这些观察结果一致，在自发性人鳞状细胞癌（SCC）中检测到NF-κ B阻断沿着JNK活化和CDK 4上调。这些发现强调了CDK 4和JNK在RelA调控表皮生长中的潜在重要性。然而，RelA抑制CDK 4水平和JNK活性的机制尚不清楚，JNK级联在异常表皮生长疾病（如SCC）中的直接作用尚未确定。 该提案的第一个目标是定义介导RelA下调CDK 4的机制。为此，我们将研究我们最近发现的RelA和CDK 4之间物理相互作用的性质和重要性。将进行系统的结构-功能研究以鉴定参与CDK 4调节和表皮细胞生长的RelA结构域。不 第二个目标是确定JNK信号级联在与NF-κ B相关的表皮稳态和瘤形成中的作用。将评估JNK途径中的功能获得或丧失对CDK 4水平和表皮生长的影响，伴或不伴NF-κ B抑制。JNK激活在肿瘤促进中的效力将通过遗传干扰方法在人表皮组织中确定。 到本资助期结束时，我们希望已经确定了NF-kappaB，CDK 4和JNK级联调节正常和肿瘤表皮组织生长的机制，并为异常细胞生长疾病（如皮肤癌）的未来分子靶点的开发提供见解。

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.