Tumor Suppressor MMAC/PTEN Inhibits Cytokine-induced NFκB Activation without Interfering with the IκB Degradation Pathway

The phosphoinositide 3-kinase (PI 3-kinase) pathway has been implicated in the activation of the proinflammatory transcription factor nuclear factor κB (NFκB). To investigate the role of this pathway in NFκB activation, we employed mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN), a natural antagonist of PI 3-kinase activity. Our results show that cytokine-induced DNA binding and transcriptional activities of NFκB were both inhibited in a glioma cell line that was stably transfected with MMAC/PTEN. The ability of interleukin-1 (IL-1) to induce inhibitor (IκB) degradation or nuclear translocation of NFκB was, however, unaffected by MMAC/PTEN expression, suggesting that PI 3-kinase utilizes another equally important mechanism to control NFκB activation. It is conceivable that NFκB is directly phosphorylated through such a mechanism because treatment with protein phosphatase 2A significantly reduced its DNA binding activity. Moreover, IL-1-induced phosphorylation of p50 NFκB was potently inhibited in MMAC/PTEN-expressing cells. Whereas the mediators of NFκB phosphorylation remain to be identified, IL-1 was found to induce physical interactions between the PI 3-kinase target Akt kinase and the IκB·IκB kinase complex. Physical interactions between these proteins were antagonized by MMAC/PTEN consistent with their potential involvement in NFκB activation. Taken together, our observations suggest that PI 3-kinase regulates NFκB activation through a novel phosphorylation-dependent mechanism. The phosphoinositide 3-kinase (PI 3-kinase) pathway has been implicated in the activation of the proinflammatory transcription factor nuclear factor κB (NFκB). To investigate the role of this pathway in NFκB activation, we employed mutated in multiple advanced cancers/phosphatase and tensin homologue (MMAC/PTEN), a natural antagonist of PI 3-kinase activity. Our results show that cytokine-induced DNA binding and transcriptional activities of NFκB were both inhibited in a glioma cell line that was stably transfected with MMAC/PTEN. The ability of interleukin-1 (IL-1) to induce inhibitor (IκB) degradation or nuclear translocation of NFκB was, however, unaffected by MMAC/PTEN expression, suggesting that PI 3-kinase utilizes another equally important mechanism to control NFκB activation. It is conceivable that NFκB is directly phosphorylated through such a mechanism because treatment with protein phosphatase 2A significantly reduced its DNA binding activity. Moreover, IL-1-induced phosphorylation of p50 NFκB was potently inhibited in MMAC/PTEN-expressing cells. Whereas the mediators of NFκB phosphorylation remain to be identified, IL-1 was found to induce physical interactions between the PI 3-kinase target Akt kinase and the IκB·IκB kinase complex. Physical interactions between these proteins were antagonized by MMAC/PTEN consistent with their potential involvement in NFκB activation. Taken together, our observations suggest that PI 3-kinase regulates NFκB activation through a novel phosphorylation-dependent mechanism. nuclear factor κB mutated in multiple advanced cancers/phosphatase and tensin homologue phosphoinositide 3-kinase IκB kinase interleukin-1 tumor necrosis factor protein phosphatase 2A Jun N-terminal kinase polyacrylamide gel electrophoresis The transcription factor NFκB1 is activated by interleukin-1 (IL-1), tumor necrosis factor (TNF), and a variety of other stress-inducing stimuli (1Baldwin A. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5579) Google Scholar, 2Siebenlist U. Franzosa G. Brown K. Annu. Rev. Cell Biol. 1994; 10: 405-455Crossref PubMed Scopus (2015) Google Scholar, 3Mercurio F. Manning A.M. Curr. Opin. Cell Biol. 1999; 11: 226-232Crossref PubMed Scopus (448) Google Scholar). In addition to its role in inflammation, NFκB has also been implicated in cellular survival, transformation, and oncogenesis (1Baldwin A. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5579) Google Scholar, 2Siebenlist U. Franzosa G. Brown K. Annu. Rev. Cell Biol. 1994; 10: 405-455Crossref PubMed Scopus (2015) Google Scholar, 3Mercurio F. Manning A.M. Curr. Opin. Cell Biol. 1999; 11: 226-232Crossref PubMed Scopus (448) Google Scholar). Predominantly a heterodimeric complex of two polypeptides (p65/RelA and p50), NFκB is physically confined to the cytoplasm through its interactions with inhibitors belonging to the IκB family of proteins (1Baldwin A. Annu. Rev. Immunol. 1996; 14: 649-681Crossref PubMed Scopus (5579) Google Scholar, 2Siebenlist U. Franzosa G. Brown K. Annu. Rev. Cell Biol. 1994; 10: 405-455Crossref PubMed Scopus (2015) Google Scholar, 3Mercurio F. Manning A.M. Curr. Opin. Cell Biol. 1999; 11: 226-232Crossref PubMed Scopus (448) Google Scholar). When phosphorylated on serine 32 and serine 36, IκBα is marked and degraded by the ubiquitin/26 S proteasome pathway liberating the NFκB heterodimer so that it may translocate to the nucleus. The signaling cascade that induces IκB degradation and thus leads to NFκB activation has recently been delineated (3Mercurio F. Manning A.M. Curr. Opin. Cell Biol. 1999; 11: 226-232Crossref PubMed Scopus (448) Google Scholar). There is compelling evidence that phosphorylation of the regulatory serines on IκBα is mediated by a 300–500-kDa multisubunit IκB protein kinase (IKK) (4Zandi E. Rothwarf D.M. Delhase M. Hayakawa M. Karin M. Cell. 1997; 91: 243-252Abstract Full Text Full Text PDF PubMed Scopus (1589) Google Scholar, 5Rothwarf D.M. Zandi E. Natoli G. Karin M. Nature. 1998; 395: 297-300Crossref PubMed Scopus (853) Google Scholar, 6Woronicz J.D. Gao X. Cao Z. Rothe M. Goeddel D.V. Science. 1997; 278: 866-869Crossref PubMed Scopus (1068) Google Scholar, 7Cohen L. Henzel W.J. Baeuerle P.A. Nature. 1998; 395: 292-296Crossref PubMed Scopus (270) Google Scholar, 8Regnier C.H. Song H.Y. Gao X. Goeddel D. Cao Z. Rothe M. Cell. 1997; 90: 373-383Abstract Full Text Full Text PDF PubMed Scopus (1072) Google Scholar, 9DiDonato J.A. Hayakawa M. Rothwarf D. Zandi E. Karin M. Nature. 1997; 388: 548-554Crossref PubMed Scopus (1913) Google Scholar, 10Mercurio F. Zhu H. Murray B.W. Shevchenko A. Bennett B.L. Li J.-w. Young D.B. Barbosa M. Mann M. Manning A. Rao A. Science. 1997; 278: 860-866Crossref PubMed Scopus (1853) Google Scholar). This kinase complex was purified to apparent homogeneity and shown to be composed primarily of the protein kinases IKKα and IKKβ as well as a protein that lacks a catalytic kinase domain known as IKKγ (4Zandi E. Rothwarf D.M. Delhase M. Hayakawa M. Karin M. Cell. 1997; 91: 243-252Abstract Full Text Full Text PDF PubMed Scopus (1589) Google Scholar, 5Rothwarf D.M. Zandi E. Natoli G. Karin M. Nature. 1998; 395: 297-300Crossref PubMed Scopus (853) Google Scholar, 6Woronicz J.D. Gao X. Cao Z. Rothe M. Goeddel D.V. Science. 1997; 278: 866-869Crossref PubMed Scopus (1068) Google Scholar, 7Cohen L. Henzel W.J. Baeuerle P.A. Nature. 1998; 395: 292-296Crossref PubMed Scopus (270) Google Scholar, 8Regnier C.H. Song H.Y. Gao X. Goeddel D. Cao Z. Rothe M. Cell. 1997; 90: 373-383Abstract Full Text Full Text PDF PubMed Scopus (1072) Google Scholar, 9DiDonato J.A. Hayakawa M. Rothwarf D. Zandi E. Karin M. Nature. 1997; 388: 548-554Crossref PubMed Scopus (1913) Google Scholar, 10Mercurio F. Zhu H. Murray B.W. Shevchenko A. Bennett B.L. Li J.-w. Young D.B. Barbosa M. Mann M. Manning A. Rao A. Science. 1997; 278: 860-866Crossref PubMed Scopus (1853) Google Scholar). The phosphorylation and degradation of IκB may not, however, be sufficient to activate NFκB. Using two different phosphoinositide 3-kinase (PI 3-kinase) inhibitors, we have previously shown that the PI 3-kinase signaling pathway is also required for NFκB activation (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Whereas wortmannin efficiently blocked IL-1-induced increases in the DNA binding activity of NFκB, a dominant-negative mutant of the p85 regulatory subunit of PI 3-kinase inhibited the ability of IL-1 to induce an NFκB-dependent reporter gene (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). More recently, Marmiroli et al. (12Marmiroli S. Bavelloni A. Faenza I. Sirri A. Ognibene A. Cenni V. Tsukada J. Koyama Y. Ruzzene M. Ferri A. Auron P.E. Toker A. Maraldi N.M. FEBS Lett. 1998; 438: 49-54Crossref PubMed Scopus (64) Google Scholar) have shown that tyrosine 479 on the type I IL-1 receptor (IL-1RI) is required for receptor interaction with PI 3-kinase. When tyrosine 479 was replaced with phenylalanine, the mutant IL-1RI lost its ability to interact with PI 3-kinase and was deficient in signaling for the activation of both PI 3-kinase and NFκB. Our recent studies have shown that TNF-induced NFκB activation also requires PI 3-kinase and that, when inhibited, PI 3-kinase potentiates TNF-induced apoptosis (13Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar). Consistent with a role for PI 3-kinase in NFκB activation and the antiapoptotic properties of NFκB, p65/RelA protected apoptosis by in with wortmannin (13Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar). other studies have shown the involvement of PI 3-kinase its Akt kinase in NFκB activation by and S. Cell. Biol. 1999; PubMed Google Scholar, J.A. D. Nature. 1999; PubMed Scopus Google Scholar, D. A. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Nature. 1999; PubMed Scopus Google Scholar, A. B.L. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Henzel W.J. Baeuerle P.A. U. S. A. 1999; PubMed Scopus Google Scholar, L. Cell. Biol. 2000; PubMed Scopus Google Scholar, E. A. J. 1997; PubMed Scopus Google Scholar). The role of PI 3-kinase in NFκB activation however, as is evidence in of J.A. D. Nature. 1999; PubMed Scopus Google Scholar, D. A. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and S. Cell. Biol. 1999; PubMed Google Scholar, L. Cell. Biol. 2000; PubMed Scopus Google Scholar) a role for it in IκB degradation and NFκB nuclear has been that, in DNA PI 3-kinase and Akt for the transcriptional activity of NFκB S. Cell. Biol. 1999; PubMed Google Scholar). The for the between the studies be to the inhibitors the of the cell these studies have implicated the PI pathway in NFκB activation, its role is a for that the of PI 3-kinase in NFκB activation. be to with in the and another be to cell with in the PI In this we a glioma cell line that lacks a natural antagonist of the PI to investigate the of PI 3-kinase in cytokine-induced NFκB activation. The of PI 3-kinase that for the activation of protein kinases such as Akt the by the phosphatase activity of MMAC/PTEN J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, U. S. A. 1999; PubMed Scopus Google Scholar). This of to be for its tumor is important for PI 3-kinase activity in X. K. U. S. A. 1998; PubMed Scopus Google I. J. U. S. A. 1998; PubMed Scopus Google Scholar). The of MMAC/PTEN as a inhibitor be for the role of PI 3-kinase in NFκB activation. Our results that PI 3-kinase is in the of DNA binding activity and potential of NFκB through a phosphorylation-dependent mechanism that is to the IκB degradation were in and in a were Jun N-terminal kinase and IκBα kinase serine or was was for gene and MMAC/PTEN was by a the multiple of were in and and transfected with the MMAC/PTEN by The glioma cell line was with the transfected cells. of were with were to cell and for MMAC/PTEN by were with and in a and to were by for were by and to and were with and the of nuclear were of proteins were by with or MMAC/PTEN-expressing were with IL-1 or for of of nuclear that were as previously (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar) were for with or was to the for the addition of the nuclear were with of the catalytic subunit of protein phosphatase 2A by a of for with the The were on polyacrylamide and by and were in and transfected the with an reporter with an IκBα or an control the to the were with and with the and were in an that the reporter was with or with were as and for with to Akt or were with a of protein and by in proteins were by and by with or were by were with were with and for activity with of as and were for were by phosphorylation was by or were in and in and the were and for in treatment with IL-1 for were and by To protein that in the we the with (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar) and this with of protein the were for the of NFκB with to protein were and by protein were by MMAC/PTEN is mutated or in a variety of J. D. K. S. J. L. M. H. Science. 1997; PubMed Scopus Google Scholar, P.A. M. H. 1997; PubMed Scopus Google Scholar). cell for MMAC/PTEN to that be for the role of PI 3-kinase in NFκB activation. the glioma cell line MMAC/PTEN and was to IL-1 and were previously to have a mutated MMAC/PTEN gene P.A. M. H. 1997; PubMed Scopus Google Scholar). IL-1 and were to the activation of PI 3-kinase and NFκB potently in with that were to by in other cell (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar). to MMAC/PTEN-expressing by with transfected with MMAC/PTEN. MMAC/PTEN as by The of PI 3-kinase known to target the protein kinase Akt to the it is activated through phosphorylation on serine and Annu. Rev. 1998; PubMed Scopus Google Scholar, Annu. Rev. 1999; PubMed Scopus Google Scholar, Cell 1999; PubMed Scopus Google Scholar). MMAC/PTEN the of PI 3-kinase the and the phosphorylation and activation of Akt J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, X. K. U. S. A. 1998; PubMed Scopus Google Scholar). and to and the phosphorylation of The of phosphorylated were in were significantly in the MMAC/PTEN-expressing cell line In and of Akt phosphorylation were in were in the MMAC/PTEN the protein of Akt its on Akt phosphorylation is to its phosphatase in the PI 3-kinase pathway as previously X. K. U. S. A. 1998; PubMed Scopus Google Scholar, H. U. S. A. 1998; PubMed Scopus Google Scholar, Y. X. D. D. P.A. 1998; Google Scholar). that when MMAC/PTEN is it is to IL-1-induced phosphorylation and activation of Akt through the of PI PI 3-kinase and Akt have been shown to be required for the activation of NFκB (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, S. Bavelloni A. Faenza I. Sirri A. Ognibene A. Cenni V. Tsukada J. Koyama Y. Ruzzene M. Ferri A. Auron P.E. Toker A. Maraldi N.M. FEBS Lett. 1998; 438: 49-54Crossref PubMed Scopus (64) Google Scholar, S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar, S. Cell. Biol. 1999; PubMed Google Scholar, J.A. D. Nature. 1999; PubMed Scopus Google Scholar, D. A. Curr. Biol. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Nature. 1999; PubMed Scopus Google Scholar, A. B.L. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, Henzel W.J. Baeuerle P.A. U. S. A. 1999; PubMed Scopus Google Scholar, L. Cell. Biol. 2000; PubMed Scopus Google Scholar, E. A. J. 1997; PubMed Scopus Google Scholar). Akt phosphorylation was efficiently inhibited in we MMAC/PTEN also NFκB activation. IL-1 and the DNA binding activity of NFκB in as by gel NFκB because be with by The ability of IL-1 and to activate NFκB was, however, inhibited in suggesting that MMAC/PTEN the potential to the DNA binding activity of NFκB It is to that the of a was the complex of NFκB, was also inhibited in To that MMAC/PTEN cytokine-induced NFκB activation, we its on the of an reporter The of this be in required NFκB activation because it was inhibited in the of the IκB Consistent with the gel IL-1-induced of the reporter gene was inhibited in of MMAC/PTEN and also to NFκB-dependent gene Taken together, these results a role for the PI 3-kinase pathway in the DNA binding and transcriptional activities of NFκB. of MMAC/PTEN in blocked the activation of both Akt and NFκB we it inhibited other IL-1-induced as To this we the of MMAC/PTEN on the ability of IL-1 to the protein kinase was and cell and for activity with as the The of activity was of treatment of with IL-1 and for the of activation and the of of in these were to in the It is that MMAC/PTEN by the PI 3-kinase pathway in activation in IL-1 In a to was also to activity equally well in both and Consistent with these two other PI 3-kinase inhibitors, wortmannin and a dominant-negative mutant of PI 3-kinase cytokine-induced activation PI have previously been shown to be in the activation of such as in factor J. M. J. Cell Biol. 1998; PubMed Scopus Google Scholar). these results that the of MMAC/PTEN on Akt and NFκB activation The phosphorylation of IκBα induces its degradation and the nuclear translocation of the and TNF-induced NFκB activation was inhibited in and we this because MMAC/PTEN with of these in NFκB activation. To our that IL-1 the degradation of IκB efficiently and with in both and NFκB was found to translocate to the treatment with apparent between and MMAC/PTEN-expressing results were when the PI 3-kinase inhibitors wortmannin and were employed suggest that MMAC/PTEN of the that to IκB degradation and NFκB nuclear and this that the PI 3-kinase pathway the DNA binding activity of NFκB through an mechanism. Our results suggest that the PI pathway regulates the DNA binding activity of NFκB. To the we the that the signaling proteins of the PI 3-kinase pathway physically interact with proteins that known to in IL-1-induced NFκB activation. Physical interactions between Akt and were recently to be important in and NFκB activation J.A. D. Nature. 1999; PubMed Scopus Google Scholar, J.A. Nature. 1999; PubMed Scopus Google Scholar). to Akt and proteins and cell of the cell that IκBα with Akt and that the two proteins physically interact with other Consistent with its degradation in or IκBα was in complex with Akt treatment with IκBα however, in Akt of IL-1 In addition to the IκB kinase IKKα was also in Akt and interactions between the proteins were when were for The of Akt with IκBα and IKKα was found to be in a and physical interactions between Akt and IκBα and or Akt and IKKα were inhibited in the cells. IL-1-induced Akt phosphorylation was also inhibited in these it is that phosphorylation of Akt is required for its interactions with IκBα and Consistent with this IL-1-induced interactions between Akt and IκBα were also inhibited in that were with the PI 3-kinase inhibitor The p50 and p65/RelA of NFκB have been shown to be phosphorylated M. E. J. 1994; PubMed Scopus Google Scholar, M. J. 1994; PubMed Scopus Google Scholar, D. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, J. V. H. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, H. S. Cell. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). our results that PI 3-kinase regulates the DNA binding activity of NFκB the IκB degradation we the that the mechanism NFκB nuclear were with by of the protein phosphatase 2A treatment of nuclear in a of IL-1-induced DNA binding activity of NFκB as by gel that the IκB and that the of was to degradation of the NFκB proteins The of on NFκB is to that with phosphatase U. S. A. 1999; PubMed Scopus Google and it a role for phosphorylation in the DNA binding activity of NFκB. It is that MMAC/PTEN the DNA binding activity of NFκB by with the that to NFκB To this we the of MMAC/PTEN on the in phosphorylation of is primarily for the DNA binding activity of NFκB. IL-1 was found to induce the phosphorylation of a with The phosphorylated was to be on in of and through the of a control for phosphorylation of p50 NFκB was significantly inhibited in cells. This the that the DNA binding activity of NFκB by with its phosphorylation on have the role of PI 3-kinase in cytokine-induced NFκB activation. Our results show that both and TNF-induced DNA binding and the transcriptional activities of NFκB were potently inhibited in a glioma cell line that stably MMAC/PTEN. The of NFκB activation was to be because MMAC/PTEN with other IL-1-induced such as that to IκBα NFκB nuclear or activation. Consistent with its role as a PI 3-kinase MMAC/PTEN inhibited the ability of IL-1 to induce Akt phosphorylation in the cell observations suggest that the PI 3-kinase pathway is for the activation of NFκB. PI 3-kinase inhibitors such as and dominant-negative of PI 3-kinase Akt have been previously to PI 3-kinase in NFκB activation (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, S. Cell. Biol. 1999; PubMed Google Scholar, J.A. D. Nature. 1999; PubMed Scopus Google J.A. Nature. 1999; PubMed Scopus Google Scholar, L. Cell. Biol. 2000; PubMed Scopus Google Scholar). Whereas PI 3-kinase and Akt required for NFκB activation, induce NFκB-dependent reporter gene when with IL-1 or (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar, S. Cell. Biol. 1999; PubMed Google Scholar). Our studies however, that NFκB-dependent gene was activated when PI were with IL-1 or (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar). that PI 3-kinase with other or to activate NFκB (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar, S.A.G. Huang J.H. Liao W.S.-L. J. Immunol. 2000; 164: 1355-1363Crossref PubMed Scopus (168) Google Scholar). The results in this and S. Cell. Biol. 1999; PubMed Google Scholar) that PI 3-kinase in the pathway that leads to IκB may its to activate NFκB by the between PI 3-kinase and IL-1 or for the of NFκB-dependent gene be to the ability of PI to with the IκB degradation mechanism of this the of two or is to be in the IL-1 signaling pathway for the activation of other transcription such as (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). Using two different we have shown that MMAC/PTEN IL-1 and NFκB. Whereas gel that MMAC/PTEN and TNF-induced increases in the DNA binding activity of NFκB, that MMAC/PTEN inhibited NFκB-dependent gene the of the reporter gene in our is by the it be in the of NFκB or when NFκB a mutant reporter gene that NFκB was to IL-1 in our studies (11Reddy S.A.G. Huang J.H. Liao W.S.-L. J. Biol. Chem. 1997; 272: 29167-29172Abstract Full Text Full Text PDF PubMed Scopus (219) Google Scholar). to that to by MMAC/PTEN that the potential of NFκB. The phosphorylation of serine on p65/RelA is an of a mechanism that regulates the transcriptional activity of NFκB D. J. Biol. Chem. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar). 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