| The NF-κB transcription factors are central mediators of many pathologic conditions, ranging from autoimmune and inflammatory disorders to cancer. Using PCR mediated cDNA subtraction screening, TAPIR was identified as a novel NF-κB target gene that is likely to be involved in such processes. TAPIR gene expression was upregulated by tetracycline-regulated expression of c-Rel in human HeLa cells and was also induced upon endogenous NF-κB activation of epithelial and lymphocytic cell lines in response to stimuli such as TNFα, LPS, or PMA/ionomycin. Functionally, TAPIR inhibited TNFα, IL-1, IKKα, IKKβ and RelA-mediated trans-activation of an IL-6 κB luciferase reporter gene. In addition, TAPIR repressed RelA-mediated activation of a stably integrated κB luciferase reporter gene in NIH3T3 cells. TAPIR had no effect on IκBα degradation nor on the sub-cellular localization of NF-κB. Whereas TAPIR could localize to the nucleus, it failed to inhibit NF-κB DNA binding in TNFα-stimulated cells. This inhibitory activity was not restricted to NF-κB, as TAPIR also repressed transactivation by c-Jun, c-Fos, p53 or Gal4-VP16 of AP-1-, mdm2-, and Gal4-luciferase reporter genes. Deletion analysis suggested that the N-terminal zinc finger-containing region of TAPIR may be necessary for inhibit on of target gene activation and that it may function as its effector domain. Interestingly, TAPIR-mediated repression of transcription was antagonized by exogenous p300/CBP or by cell treatment with the HDAC inhibitor TSA. Importantly, inhibition of NF-κB-mediated gene activation by TAPIR sensitized cells to apoptosis induced by TNFα, or Fas receptor cross-linking. In light of the high levels of TAPIR gene expression in immune tissues and PBLs these results point to a role for TAPIR in transcriptional regulation and the control of apoptotic and inflammatory responses. |
