Down syndrome candidate region 1 increases the stability of the IkappaBalpha protein: implications for its anti-inflammatory effects.
Down syndrome candidate region 1 (DSCR1), an endogenous inhibitor of calcineurin, inhibits the expression of genes involved in the inflammatory response. To elucidate the molecular basis of these anti-inflammatory effects, we analyzed the role of DSCR1 in the regulation of NF-kappaB transactivation using glioblastoma cells stably transfected with DSCR1.4 or its truncation mutants (DSCR1.4-(1-133) and DSCR1.4-(134-197)). Overexpression of DSCR1.4 significantly attenuated the induction of cyclooxygenase-2 (COX-2) expression by phorbol 12-myristate 13-acetate (PMA) via a calcineurin-independent mechanism. Experiments using inhibitors of the signaling molecules for NF-kappaB activation showed that NF-kappaB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-kappaB as well as PMA-induced activation of NF-kappaB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IkappaBalpha; however, DSCR1.4 significantly decreased the basal turnover rate of IkappaBalpha and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IkappaBalpha as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-kappaB-mediated transcriptional activation by stabilizing its inhibitory protein, IkappaBalpha.
Kim
Young Sun
YS
Department of Pharmacology, Catholic University of Korea, Seoul 137-701, Korea.
Cho
Kyung-Ok
KO
Lee
Hong Joon
HJ
Kim
Seong Yun
SY
Sato
Yasufumi
Y
Cho
Young-Jin
YJ
D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000378:metabolism; D004268:DNA-Binding Proteins; D004314:Down Syndrome / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D020672:I-kappa B Proteins / Q000737:chemistry* / Q000378:metabolism; D007249:Inflammation; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000502:physiology*; D007700:Kinetics; D009124:Muscle Proteins / Q000235:genetics* / Q000502:physiology*; D000072000:NF-KappaB Inhibitor alpha; D013755:Tetradecanoylphorbol Acetate; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection
D000893:Anti-Inflammatory Agents; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C000606204:NFKBIA protein, human; C108612:RCAN1 protein, human; D000072000:NF-KappaB Inhibitor alpha; D051546:Cyclooxygenase 2; D013755:Tetradecanoylphorbol Acetate