| Budget Amount *help |
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
PDLIM2 is a nuclear LIM protein that binds to and inhibits the activity of STAT4 transcription factor. In this study, we have demonstrated that PDLIM2 also negatively regulates the activity of NF-kB transcription factor, acting as a nuclear ubiquitin E3 ligase toward the p65 subunit of NF-KB (Tanaka, et. al., Nat. Immuno1. 8, 584, 2007). PDLIM2 binds to p65 and promotes p65 polyubiquitination through its LIM domain. In addition, PDLIM2 targets p65 to discrete intranuclear compartments called PML nuclear bodies. PML nuclear bodies are nuclear proteolytic centers where proteasomal components are concentrated. Polyubiquitinated p65 is ultimately degraded by proteasome in this compartment. A PDLIM2 mutant lacking the PDZ domain fails to target p65 to nuclear bodies, suggesting that PDLIM2 mediates intranuclear trafficking of p65 through its PDZ domain. PDLIM2 deficiency results in larger amounts of nuclear p65, defective p65 ubiquitination and augmented production of proinflammatory cytokines in response to TLR ligands, such as LPS and CpG-DNA. These findings delineate a novel pathway by which PDLIM2 terminates NF-kB activation through intranuclear sequestration and subsequent degradation. Moreover, we have shown that PDLIM2 can also inhibit both IRF3 and IRF7-mediated transactivation in luciferase assay with IFNIβ or IFNα□promoter-driven reporter construct, respectively. Among LIM protein family, Ril (PDLIM4), elfin (PDLIM1) and ALP (PDLIM3) are the most closely related with PDLIM2Moreover, we have found that these LIM proteins could inhibit NF-KB-mediated transactivation in luciferase assay with reporter containing NF-kB binding site. These findings suggest that LIM proteins are the novel family that negatively regulates signal transductions in immune system.
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