Primary Study Of CREB4 Translocation Mechanism From Cytoplasm To Nucleus

Signal-transduction pathways converge ultimately at the level of transcriptional activation to produce specific patterns of gene expression in response to environmental stimuli. The initiation of transcription mediated by these signaling pathways is regulated by the coordinate expression and/or activation of specific transcription factors that bind to the control regions of genes. Specific insights into the mechanisms underlying transcriptional activation have recently arisen from studies of the structure and functions of these transcription factors. The mammalian CREB/ATF family represents a large group of basic-region leucine zipper (bzip) transcription factors with rather diverse physiological functions. Defects in the apoptotic signaling pathway are often associated with uncontrolled cell proliferation, high mutation rate and malignant transformation. Transcriptional regulators ATF/CREB family have diverse functions in controlling cell proliferation and apoptosis. Aberrant expression of these proteins causes abnormal progression, cell apoptosis and death.CREB4 is a member of human CREB/ATF family. Subcellular location of CREB4 and CREB4^1-279 showed that a fusion protein of GFP and full-length CREB4 was localized in cytoplasm, whereas the fusion protein of GFP and a deletion mutant lacking the C-terminal putative transmembrane domain was translocated in nucleus, which suggested that C-terminal of CREB4 protein is associated with the process of translocation of CREB4 from cytoplasm to nucleus.Constructing CREB4^215-279 and CREB^2-5-395 fusion protein with the entire prokaryotic LexA protein respectively , Yeast two-hybrid system revealed two proteins, TPR and karyopherin α 2 ,may associate with CREB4(215-279). TPR was a nuclear pore complex associated protein, karyopherin a 2 was concerned with the Karyopherin α 2 β 1 pathways mediated by receptors to assist the translocation of proteins from cytoplasm to nucleous, which suggusted that it may be associated with translocation of CREB4.Co-location showed that CREB4 and karyopherin α 2 were co-located in cytoplasm, whereas CREB4^1-279 and karyopherin α 2 were co-located in nucleus. These results suggested that CREB4 first combined with karyopherin α 2, followed by the C-terminal cleavage, finally translocation into nucleus to activate gene transcription.