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.
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