Role of NIK Activation in Melanoma Progression

描述（由申请方提供）：黑色素瘤发生中的一个关键事件是关键细胞调节基因突变，导致肿瘤抑制因子和血管生成和生长调节因子内源性表达缺失。 在肿瘤发生过程中，核因子-κ B（NF-κ B）的组成性激活已在我们的实验室和其他一些实验室中被广泛记录。 我们已经证明，在黑色素瘤肿瘤进展过程中，IKKalpha-beta被组成性激活，导致NF-κ B的核激活，这反过来又有助于逃避肿瘤细胞的凋亡和永生化。 我们已经观察到，与NF-κ B的活化相协调的是NF-κ B诱导激酶NIK的活化增强。 我们假设NIK在肿瘤进展过程中被上游效应物激活，这些事件导致NF-κ B介导的转录和肿瘤进展增强。 我们建议表征NIK和NF-kappaB激活的机制，并根据我们的研究结果开发探索黑色素瘤新的治疗干预方案。 该提议的具体目的是1）确定在黑色素瘤肿瘤进展期间NIK组成性激活的机制; 2）开发消除组成性NIK和NF-κ活性并阻断肿瘤生长的方法; 3）确定发生NIK组成性激活的黑色素瘤肿瘤进展阶段。 本提案中描述的工作应该为设计用于干预显示组成性NIK激活的肿瘤的进展和生长的治疗试剂的开发提供见解。

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.