Abnormal NF-kappaB signaling pathway with enhanced susceptibility to apoptosis in immortalized keratinocytes
Abstract
The transcriptional activation and proper regulation of NF-kappaB is known to be important to the apoptotic resistant phenotype of epidermal-derived keratinocytes. By comparing and contrasting the responses of normal foreskin-derived keratinocytes versus an immortalized skin-derived keratinocyte cell line (i.e. HaCaT cells), several molecular defects involving NF-kappaB signaling pathway were delineated in the immortalized keratinocytes. While exposure to IFN-gamma plus TPA produces growth arrest in both normal and immortalized keratinocytes, with rapid phosphorylation of MEKKI and recruitment of distinctive protein kinase C isoforms into the signalosome complex, subsequent molecular events necessary for NF-kappaB activation were abnormal in HaCaT cells. This disrupted NF-kappaB activation in HaCaT cells was accompanied by enhanced susceptibility to UV-light induced apoptosis, which was associated with elevated levels of E2F-1 and decreased TRAF1/TRAF2 levels. Additional defects in HaCaT cells included markedly diminished levels of IKKbeta (and lack of induction of kinase activity) in response to inflammatory stimuli, a failure of p21(WAF1/CIP1) to associate with CDK2, and a decreased association between p65 and p300. These stu...Continue Reading
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