| The NF-kappaB family of transcription factors is involved in the regulation of many normal cellular processes including inflammation, immune response, and cell growth and survival. Additionally, NF-kappaB has been implicated in many human diseases, including heart disease, chronic inflammation, neurodegenerative disorders, and cancer.;Misregulation of REL, an NF-kappaB transcription factor, has been described in several human lymphoid malignancies. Genetic alterations in REL have been found in human B-cell lymphomas in the form of amplifications, C-terminal deletions, and point mutations. Moreover, overexpression of REL can malignantly transform chicken lymphoid cells. These findings implicate REL in human oncogenesis, and thus, the goal of this research is to further characterize REL functional domains so as to further understand how REL contributes to lymphoid malignancy.;REL has a conserved N-terminal DNA-binding/dimerization domain called the Rel homology domain (RHD) and a C-terminal transactivation domain (TAD). Herein, residues (amino acids [aa] 323-422) between the RHD and TAD are defined as a REL inhibitory domain (RID) because deletion of these sequences increases both REL transactivation and DNA binding. Furthermore, two REL mRNA splice variants that encode proteins with alterations near RID are characterized: one lacking exon 9 sequences (aa 308-330; RELDelta9) and one with an exonized Alu fragment (REL+Alu). Deletion of RID or exon 9-encoded residues increases three activities of REL: transactivation by GAL4-REL, transactivation by full-length REL from certain kappaB site-containing promoters, and DNA binding by REL. Deletion of RID does not affect REL's ability to transform chicken spleen cells. RT-PCR analysis indicates that the RELDelta9 splice variant is preferentially expressed in lymphoma cell lines and primary DLBCLs, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors. A two-hybrid screen identifies RanBPM as a protein that can specifically interact with exon 9-encoded residues. In addition, the interaction of REL with the coactivator p300 is investigated. A comprehensive analysis of mRNAs encoding NF-kappaB signaling pathway proteins reveals that many NF-kappaB signaling components undergo alternative splicing. Several of these splice variants can alter normal NF-kappaB signaling and may play a role in NF-kappaB-associated diseases. |
