**11. The NFκB (NF-kappaB) pathway**

The NFκB family in mammals contains 5 members – p105/p50 (NFκB1), p100/p52 (NFκB2), RelA (p65), RelB and c-Rel (J-206, 207). The canonical activation of NFκB pathway involves TNFα stimulation resulting in the subsequent phosphorylation/activation of IKK (IκB kinase). In turn, IKK-mediated phosphorylation of IκB leading to ubiquitination of IκB and its proteosomal degradation, releasing the NFκB complex which activates a host of target genes [116,117]. The type of genes that get trans-activated depends on the composition of activated NFκB complex. For instance, complexes containing c-Rel activates pro-apoptotic genes (Dr4/ Dr5, Bcl-x) and inhibits anti-apoptotic genes (cellular inhibitor of apoptosis (cIAP1, cIAP2), survivin). Complexes containing RelA inhibits the expression of DR4/DR5 and upregulates caspase 8, cIAP1 and cIAP2 [118].

NFκB is activated in various tumors including melanomas and distinct mechanisms have been proposed for the elevated levels of NFκB activity in melanomas. Activation of NFκB in melanomas is also linked to the loss of E-cadherin, a frequent event in melanoma transforma‐ tion [119]. NIK (NFκB interacting kinase), an activator of IKK is overexpressed in melanoma cells while compared to normal cells. The major contribution of NFκB in melanoma develop‐ ment and progression relates to its function as an important regulator of survival and apop‐ tosis. A study by Meyskens at al demonstrated that in metastatic melanoma cells, an increase in DNA binding activity of NFκB is associated with an increased expression of p50 and RelA resulting in increased expression of anti-apoptotic regulators. Also the expression of c-Rel, the transcriptional activator of pro-apoptotic genes is markedly in melanoma cells compared with normal melanocytes [120]. Strong p50 nuclear staining also correlated with poor prognosis in melanoma patients [121]. Besides eliciting anti-apoptotic activities NFκB mediates the transcription of MMP2 and MMP9 [121,122]. Overexpression of MMPs is associated with tumor invasion, metastasis and angiogenesis.
