Role of NIK Activation in Melanoma Progression

描述(申请人提供)：黑色素瘤发展中的一个关键事件是关键细胞调控基因的突变，导致肿瘤抑制基因的丧失以及血管生成和生长调控因子的内源性表达。核因子-kappaB(核因子-kappaB)在肿瘤发生过程中的结构性激活在我们的实验室和其他一些实验室中已经被广泛地记录下来。我们已经证明，在黑色素瘤肿瘤进展过程中，IKKalpha-β被结构性激活，导致核转录因子-kappaB的核激活，进而促进肿瘤细胞逃避凋亡和永生化。我们观察到，与核因子-kappaB的激活相协调的是核因子-kappaB诱导的激酶NIK的增强激活。我们假设NIK在肿瘤进展过程中被上游效应分子激活，这些事件导致核因子-kappaB介导的转录增强和肿瘤进展。我们建议表征NIK和NF-kappaB的激活机制，并根据我们的发现开发出探索新的黑色素瘤治疗干预措施的方案。这项建议的具体目标是：1)确定在黑色素瘤肿瘤进展过程中Nik被结构性激活的机制；2)开发去除结构性Nik和核因子-kkappa活性并阻止肿瘤生长的方法；3)确定在黑色素瘤肿瘤进展中发生结构性激活的Nik的阶段。这项建议中描述的工作应该为开发治疗试剂提供洞察力，这些试剂旨在干预表现出结构性NIK激活的肿瘤的进展和生长。

DESCRIPTION (provided by applicant): A key event in the development of melanoma is the mutation of key cell regulatory genes resulting in loss of tumor suppressors and endogenous expression of angiogenic and growth regulatory factors. The constitutive activation of nuclear factor-kappa beta (NF-kappaB) during tumorigenesis has been extensively documented in our lab, and a number of other laboratories. We have demonstrated that during melanoma tumor progression, IKKalpha-beta become constitutively activated, leading to nuclear activation of NF-kappaB, which in turn facilitates escape from apoptosis and immortalization of tumor cells. We have observed that coordinate with the activation of NF-kappaB is enhanced activation of the NF-kappaB inducing kinase, NIK. We hypothesize that NIK is activated by an upstream effector during tumor progression and these events lead to enhanced NF-kappaB mediated transcription and tumor progression. We propose to characterize the mechanism for the activation of NIK and NF-kappaB, and to develop protocols which explore new therapeutic intervention for melanoma based upon our findings. The specific aims of this proposal are 1) To determine the mechanism by which NIK is constitutively activated during melanoma tumor progression; 2) To develop approaches to ablate constitutive NIK and NF-kkappa activity and block tumor growth; 3) To determine the stage in melanoma tumor progression where constitutive activation of NIK occurs. The work described in this proposal should provide insight for the development of therapeutic reagents designed to intervene in the progression and growth of tumors showing constitutive NIK activation.