Down Syndrome Candidate Region 1 Increases the Stability of the IκBα Protein

Abstract

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-κB 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-κB activation showed that NF-κB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-κB as well as PMA-induced activation of NF-κB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IκBα; however, DSCR1.4 significantly decreased the basal turnover rate of IκBα and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IκBα as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-κB-mediated transcriptional activation by stabilizing its inhibitory protein, IκBα. 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-κB 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-κB activation showed that NF-κB is responsible for the induction of COX-2. Full-length and truncated DSCR1.4 decreased the steady-state activity of NF-κB as well as PMA-induced activation of NF-κB, which correlated with attenuation of COX-2 induction. DSCR1.4 did not affect the PMA-stimulated phosphorylation or degradation kinetics of IκBα; however, DSCR1.4 significantly decreased the basal turnover rate of IκBα and consequently up-regulated its steady-state level. In the same context, knockdown of endogenous DSCR1.4 increased the turnover rate of IκBα as well as COX-2 induction. These results suggest that DSCR1 attenuates NF-κB-mediated transcriptional activation by stabilizing its inhibitory protein, IκBα. The human Down syndrome critical region 1 gene was isolated from chromosome 21q22, and it was thought to be located within a region that is involved in the expression of the Down syndrome phenotype (1Fuentes J.J. Pritchard M.A. Planas A.M. Bosch A. Ferrer I. Estivill X. Hum. Mol. Genet. 1995; 4: 1935-1944Crossref PubMed Scopus (224) Google Scholar). Refined maps of chromosome 21 revealed that the gene lies just outside this region (2Strippoli P. Lenzi L. Petrini M. Carinci P. Zannotti M. Genomics. 2000; 64: 252-263Crossref PubMed Scopus (65) Google Scholar), and the name of the gene was modified to Down syndrome candidate region 1 (DSCR1) 2The abbreviations used are: DSCR1, Down syndrome candidate region 1; NF-κB, nuclear factor κB; IκB, inhibitors of κB; IKK, IκB kinase; CK2, casein kinase 2; COX-2, cyclooxygenase-2; IL-1β, interleukin-1β; PMA, phorbol 12-myristate 13-acetate; TNF-α, tumor necrosis factor-α; PKC, protein kinase C; ERK1/2, extracellular signal-related kinase 1/2; GFP, green fluorescent protein; GST, glutathione S-transferase; siRNA, small interfering RNA; MEK1, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1. (3Fuentes J.J. Pritchard M.A. Estivill X. Genomics. 1997; 44: 358-361Crossref PubMed Scopus (164) Google Scholar). DSCR1 encodes a protein that binds to the catalytic subunit of calcineurin, inhibiting its phosphatase activity (4Fuentes J.J. Genesca L. Kingsbury T.J. Cunningham K.W. Perez-Riba M. Estivill X. de la Luna S. Hum. Mol. Genet. 2000; 9: 1681-1690Crossref PubMed Google Scholar). Consequently, it is also called modulatory calcineurin-interacting protein 1 or calcipressin 1 to reflect this function (5Rothermel B.A. Vega R.B. Williams R.S. Trends Cardiovasc. Med. 2003; 13: 15-21Crossref PubMed Scopus (144) Google Scholar). The DSCR1 gene consists of seven exons: exons 1–4 can be alternatively spliced, resulting in four different transcripts (denoted DSCR1.1 through DSCR1.4). DSCR1.1 and DSCR1.4 are widely expressed, particularly in the central nervous system, skeletal muscle, and heart. However, DSCR1.2 has been detected only in fetal liver and brain, and DSCR1.3 has not been detected in any tissue (5Rothermel B.A. Vega R.B. Williams R.S. Trends Cardiovasc. Med. 2003; 13: 15-21Crossref PubMed Scopus (144) Google Scholar, 6Harris C.D. Ermak G. Davies K.J. CMLS Cell. Mol. Life Sci. 2005; 62: 2477-2486Crossref PubMed Scopus (94) Google Scholar). Elucidation of the functional roles of DSCR1 in neuronal tissue is important because elevated levels of this protein have been implicated in the pathogenesis of neurodegenerative diseases such as Alzheimer disease and Down syndrome (4Fuentes J.J. Genesca L. Kingsbury T.J. Cunningham K.W. Perez-Riba M. Estivill X. de la Luna S. Hum. Mol. Genet. 2000; 9: 1681-1690Crossref PubMed Google Scholar, 7Cook C.N. Hejna M.J. Magnuson D.J. Lee J.M. J. Alzheimer's Dis. 2005; 8: 63-73Crossref PubMed Scopus (55) Google Scholar, 8Ermak G. Morgan T.E. Davies K.J. J. Biol. Chem. 2001; 276: 38787-38794Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Recent studies in which the DSCR1 gene was overexpressed in endothelial cells showed that DSCR1 down-regulates transcription of several pro-inflammatory factors and enzymes (9Hesser B.A. Liang X.H. Camenisch G. Yang S. Lewin D.A. Scheller R. Ferrara N. Gerber H.P. Blood. 2004; 104: 149-158Crossref PubMed Scopus (134) Google Scholar, 10Minami T. Horiuchi K. Miura M. Abid M.R. Takabe W. Noguchi N. Kohro T. Ge X. Aburatani H. Hamakubo T. Kodama T. Aird W.C. J. Biol. Chem. 2004; 279: 50537-50554Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 11Yao Y.G. Duh E.J. Biochem. Biophys. Res. Commun. 2004; 321: 648-656Crossref PubMed Scopus (63) Google Scholar, 12Minami T. Miura M. Aird W.C. Kodama T. J. Biol. Chem. 2006; 281: 20503-20520Abstract Full Text Full Text PDF PubMed Scopus (64) Google Scholar). In addition, the expression of DSCR1 is up-regulated by mitogens (9Hesser B.A. Liang X.H. Camenisch G. Yang S. Lewin D.A. Scheller R. Ferrara N. Gerber H.P. Blood. 2004; 104: 149-158Crossref PubMed Scopus (134) Google Scholar, 10Minami T. Horiuchi K. Miura M. Abid M.R. Takabe W. Noguchi N. Kohro T. Ge X. Aburatani H. Hamakubo T. Kodama T. Aird W.C. J. Biol. 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J. Infect. Dis. 2005; 192: 901-912Crossref PubMed Scopus (39) Google Scholar), depolarization (10Minami T. Horiuchi K. Miura M. Abid M.R. Takabe W. Noguchi N. Kohro T. Ge X. Aburatani H. Hamakubo T. Kodama T. Aird W.C. J. Biol. Chem. 2004; 279: 50537-50554Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 16Cano E. Canellada A. Minami T. Iglesias T. Redondo J.M. J. Biol. Chem. 2005; 280: 29435-29443Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar), and oxidative stress (17Crawford D.R. Leahy K.P. Abramova N. Lan L. Wang Y. Davies K.J. Arch. Biochem. Biophys. 1997; 342: 6-12Crossref PubMed Scopus (117) Google Scholar), all of which are frequently implicated in the initiation and maintenance of the inflammatory process. Therefore, DSCR1 is likely to play a significant role as a negative regulatory element in the inflammatory reaction. Nuclear factor κB (NF-κB) is a transcription factor involved in the regulation of many cellular target genes that play a central role in immune and inflammatory response (18Pahl H.L. Oncogene. 1999; 18: 6853-6866Crossref PubMed Scopus (3448) Google Scholar). In resting cells, most NF-κB dimers are sequestered in the cytoplasm through association with inhibitory proteins known as inhibitors of κB (IκB), of which IκBα is the best characterized. NF-κB-activating signals generated by stimulation with mitogens or cytokines result in rapid degradation of IκBα, allowing NF-κB to localize to the nucleus, where it acts on its target genes. This stimulation-induced IκBα degradation is initiated by phosphorylation of IκBα at serines 32 and 36 by a large IκB kinase (IKK) complex (IKKα·IKKβ·IKKγ·NEMO), which labels IκBα for degradation by the ubiquitin/proteasome pathway (18Pahl H.L. Oncogene. 1999; 18: 6853-6866Crossref PubMed Scopus (3448) Google Scholar, 19Chen F.E. Ghosh G. 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These studies that regulation of the basal turnover of IκBα is of NF-κB we the molecular basis of the by which DSCR1 inhibits the expression of genes with This for the that DSCR1.4 the basal turnover rate of IκBα and consequently attenuates the steady-state and transcriptional activity of NF-κB in human glioblastoma In addition, we that this of the NF-κB pathway by DSCR1.4 is significant by that of DSCR1.4 induction of the NF-κB target genes cyclooxygenase-2 (COX-2) and which by phorbol 12-myristate 13-acetate (PMA) or pro-inflammatory and IL-1β, kinase and tumor necrosis from PMA, and from for COX-2 was from for NF-κB protein kinase IκBα and from for IκBα, and from and glioblastoma cells from The cells in with and fetal an of at cells in a and for in and for with fetal to COX-2 induction with or for the in the In cells with inhibitors of signaling molecules for IκBα turnover cells for the in the of the of the and to as DSCR1.4 protein an or C-terminal green fluorescent protein human DSCR1.4 was by and the or for as for and and for and To for expression of proteins or truncated DSCR1.4 the and of the for as for and for the DSCR1.4 with a C-terminal to acid and and for the DSCR1.4 with an to acid and The of IκBα at and or at and generated by PubMed Scopus Google Scholar). The the to IκBα The used for the of and and the The and C-terminal for the expression and To an expression for the glutathione PEST of IκBα a truncated IκBα was using and The and the and of The of all by of of cells transfected with of the DSCR1.4 or with an using to the for using a The cells in with of DSCR1.4 in these cells by not DSCR1.4 small interfering used was The and negative from In for COX-2 induction cells in a transfected with the using to the the cells with for and for In for IκBα turnover the cells with of and of or the cells with as for IκBα turnover NF-κB was from and a from in a and transfected with of and of using cells with the for which activity was with a using a to the on the basis of of and In cells with the The to and protein expression was for by the of 1 and in inhibitor been by the proteins from the by with in phosphorylation of the PEST of IκBα by CK2, in kinase 1 and 1 inhibitor The was in a with 1 of protein as a in a of of kinase The by the of of and for at The was by the of and the to the in an of 1 and inhibitor been by the with and for at The proteins by or and to The for 1 at in casein in was with in casein in The with with and using the The was analyzed using an DSCR1.4 PMA-induced COX-2 via a the of elevated DSCR1 levels on COX-2 we generated of the by with expression for DSCR1 proteins with at the or or with a as a The basal of COX-2 expression in these was by not induction of COX-2, cells with the for In with studies in endothelial (9Hesser B.A. Liang X.H. Camenisch G. Yang S. Lewin D.A. Scheller R. Ferrara N. Gerber H.P. Blood. 2004; 104: 149-158Crossref PubMed Scopus (134) Google Scholar, 11Yao Y.G. Duh E.J. Biochem. Biophys. Res. Commun. 2004; 321: 648-656Crossref PubMed Scopus (63) Google Scholar), the induction of COX-2 was attenuated in cells transfected with or with This induction of COX-2 expression was also by the inhibitors and that by DSCR1 a role in this process. In COX-2 was by the induction was only by and not by or by with inhibitors These results that DSCR1 PMA-induced COX-2 expression via a calcineurin-independent mechanism. To these cells stably transfected with an expression for DSCR1.4 a and for COX-2 in of DSCR1.4 attenuated and PMA-induced COX-2 inhibitors only COX-2 of DSCR1.4 PMA-induced COX-2 we knockdown with endogenous transfected with in a region of a in DSCR1.4 levels using not this to the of decreased endogenous DSCR1.4 levels on COX-2 induction by knockdown of DSCR1.4 COX-2 resulting in a in its expression in cells transfected with DSCR1.4 with negative NF-κB by the basis of the of of DSCR1.4 by M. Sato Y. Arch. Biochem. Biophys. 2005; PubMed Scopus Google Scholar), we generated truncated of DSCR1.4 a C-terminal region or an region and with or a for cells with in and COX-2 expression by and Overexpression of DSCR1 inhibits the expression of genes with or such as COX-2, protein 1 tissue factor 1 and 1 (9Hesser B.A. Liang X.H. Camenisch G. Yang S. Lewin D.A. Scheller R. Ferrara N. Gerber H.P. Blood. 2004; 104: 149-158Crossref PubMed Scopus (134) Google Scholar, 10Minami T. Horiuchi K. Miura M. Abid M.R. Takabe W. Noguchi N. Kohro T. Ge X. Aburatani H. Hamakubo T. Kodama T. Aird W.C. J. Biol. Chem. 2004; 279: 50537-50554Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 11Yao Y.G. Duh E.J. Biochem. Biophys. Res. Commun. 2004; 321: 648-656Crossref PubMed Scopus (63) Google Scholar). is that transcription of these genes is by NF-κB (18Pahl H.L. Oncogene. 1999; 18: 6853-6866Crossref PubMed Scopus (3448) Google Scholar). Therefore, we a to DSCR1.4 inhibits the transcriptional activity of and transfected with an with increased activity to a in the and that of However, the of the cells with the at and stimulation with NF-κB activity and because of DSCR1 or Y. S. H. J. S. Y. and we used in encodes a region that is to all DSCR1 Therefore, this be of for the of other of of NF-κB COX-2 we of NF-κB activity by DSCR1.4 is responsible for the attenuation of COX-2 induction. signal that to induction of COX-2 expression stimulation with the inhibitors of signal molecules involved in COX-2 expression Cell. 2005; PubMed Scopus Google Scholar, E. S. F. C. J. 2000; PubMed Scopus Google Scholar, R. J. 2000; 279: Google Scholar, K. S. A. T. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar), and the induction of COX-2 of PKC, MEK1, and NF-κB and are signal molecules of NF-κB The for activation of NF-κB is the degradation of the different IκB IκBα a role in PMA-induced activation of NF-κB M.J. G. J. Mol. Cell. Biol. 1999; PubMed Google Scholar, J. J. M.R. R. S. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, we the of inhibitors of and on the degradation of IκBα stimulation with and significantly IκBα degradation and that and are of we and activation is by PMA-stimulated degradation or phosphorylation of was not decreased in In addition, PMA-stimulated phosphorylation at of IκBα was not by that DSCR1 a of IκBα phosphorylation in NF-κB-activating DSCR1 the and the of we PMA-stimulated degradation of IκBα is by the of IκBα degradation in cells was with that in cells stimulation with and stimulation in a rapid of IκBα in and However, the of IκBα in cells was that in cells the The steady-state of IκBα was elevated by in cells with To the in IκBα levels the is to a in the stimulation-induced degradation rate of IκBα, we the of the of IκBα in and the of IκBα in and cells not significantly we the basal turnover rate of IκBα in the same for the cells with The protein of IκBα was for in and the IκBα in cells was that in cells was a in basal IκBα degradation in these of DSCR1.4 IκBα by an and to endogenous DSCR1.4 has a role in the regulation of IκBα In addition, we also phosphorylation of IκBα is involved in the by which DSCR1.4 IκBα these cells with DSCR1.4 and an expression which has a at and The degradation of endogenous IκBα and was with knockdown of DSCR1.4 increased the rate of IκBα degradation and that endogenous DSCR1.4 an important role in IκBα protein the of was also from to and that this function of DSCR1.4 not phosphorylation of IκBα at and we phosphorylation a role in the of the IκBα we cells with DSCR1.4 and which has a at and these residues are the most critical phosphorylation for R. P. C. S. J. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, N. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar). in the of the increased the of IκBα by with that of endogenous IκBα. However, the of was from to by with DSCR1.4 and these results that knockdown of DSCR1.4 the of the IκBα protein by a that is of and phosphorylation of IκBα. with DSCR1.4 decreased the steady-state expression levels of endogenous IκBα and by and These results suggest that endogenous DSCR1.4 a significant role in the of IκBα. DSCR1.4 of IκBα we DSCR1.4 inhibits phosphorylation of IκBα. we in using as a in the of from cells stably transfected with and with the analyzed by with in and of DSCR1.4 and its truncation mutants increased the phosphorylation of The of phosphorylation was by of phosphorylation with we in using a from DSCR1.4 cells to the of knockdown of DSCR1.4 on phosphorylation of IκBα. of DSCR1.4 decreased DSCR1.4 and NF-κB signaling that NF-κB at critical in which IκB proteins are by a the elevated steady-state of IκBα in the be to NF-κB activation by signals and the expression of NF-κB target genes. To this we the of DSCR1.4 and on the expression of COX-2 and stimulation with and TNF-α, in DSCR1.4 and expression of target genes. In addition, DSCR1.4 attenuated the basal of expression its truncated also induction of COX-2 expression by or with these significantly attenuated activity that was with or DSCR1 has been to the expression of genes with a by (9Hesser B.A. Liang X.H. Camenisch G. Yang S. Lewin D.A. Scheller R. Ferrara N. Gerber H.P. Blood. 2004; 104: 149-158Crossref PubMed Scopus (134) Google showed that these anti-inflammatory are by of signaling by DSCR1, the this DSCR1 the induction of of genes and the expression of these genes with These suggest the that DSCR1 other signal that inflammatory gene this by and knockdown of DSCR1.4 because its expression is elevated by inflammatory such as M. M. K. I. Sato Y. J. Res. 2004; PubMed Scopus Google and oxidative stress (17Crawford D.R. Leahy K.P. Abramova N. Lan L. Wang Y. Davies K.J. Arch. Biochem. Biophys. 1997; 342: 6-12Crossref PubMed Scopus (117) Google Scholar). The results of this that DSCR1.4 attenuates COX-2 induction by inhibiting for a of for DSCR1.4 in that DSCR1.4 also the activity of NF-κB and the induction of COX-2. suggest that different of DSCR1.4 be involved in these on the basis of the of DSCR1.4 with the inhibitory of DSCR1.4 on COX-2 of COX-2 induction was the region by of DSCR1 is for to and of M. Sato Y. Arch. Biochem. Biophys. 2005; PubMed Scopus Google Scholar, B. G. F. T. Proc. Natl. Acad. Sci. U. S. A. 2005; PubMed Scopus Google Scholar). However, the truncated protein this region and the activity of NF-κB and COX-2 induction with important is DSCR1 activation of of NF-κB by IκBα is the that NF-κB In this we that the of IκBα in the of and the steady-state of IκBα increased in cells stably transfected with In the same context, knockdown of endogenous DSCR1.4 decreased IκBα degradation is through phosphorylation have been on IκBα, the phosphorylation located at and J. Mercurio F. Rosette C. Wu-Li J. Suyang H. Ghosh S. Karin M. Mol. Cell. Biol. 1996; 16: 1295-1304Crossref PubMed Google and the phosphorylation located in the PEST region M.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). However, the pathway not to be in cells because PMA-induced phosphorylation at and degradation of IκBα not the in IκBα by knockdown of was not by the of and of the PEST region by is a well that the basal turnover of IκBα M.P. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). However, phosphorylation also did not to be by the of and did not the decreased steady-state of IκBα and the elevated turnover rate of IκBα that was by the knockdown of endogenous In addition, we have that of DSCR1.4 or its truncation mutants phosphorylation of IκBα at using an in kinase a in activity to DSCR1.4 was in a kinase using the not On the basis of these we suggest that DSCR1.4 the degradation of IκBα by an and studies have the of NF-κB has been to with other signaling molecules such as T. Siebenlist U. J. 1996; Google and B. M.J. J. 1995; Google Scholar, A. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google to the NF-κB activation of NF-κB through and signaling B. 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A. M. J. 2005; PubMed Scopus Google Scholar). These suggest that DSCR1 be a target for of these neurodegenerative In this has that DSCR1.4 inhibits IκBα and have anti-inflammatory The by which DSCR1.4 inhibits the basal turnover rate of IκBα and its in diseases to be in