Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser529 Is Controlled by Casein Kinase II

Nuclear factor κB (NF-κB)/Rel transcription factors are key regulators of a variety of genes involved in immune and inflammatory responses, growth, differentiation, apoptosis, and development. In unstimulated cells, NF-κB/Rel proteins are sequestered in the cytoplasm by IκB inhibitor proteins. Many extracellular stimuli, such as tumor necrosis factor α (TNFα), cause rapid phosphorylation of IκB at N-terminal serine residues leading to ubiquitination and degradation of the inhibitor. Subsequently, NF-κB proteins translocate to the nucleus and activate gene expression through κB response elements. TNFα, as well as certain other stimuli, also induces the phosphorylation of the NF-κB proteins. Previously, we have shown that TNFα induces RelA/p65 phosphorylation at serine 529 and that this inducible phosphorylation increases NF-κB transcriptional activity on an exogenously supplied reporter (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). In this report, we demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFα-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IκBα and p65 inhibits p65 phosphorylation by CKII and that degradation of IκBα allows CKII to phosphorylate p65 to increase NF-κB transactivation potential. These data may explain the ability of CKII to modulate cell growth and demonstrate a mechanism whereby CKII can function in an inducible manner. Nuclear factor κB (NF-κB)/Rel transcription factors are key regulators of a variety of genes involved in immune and inflammatory responses, growth, differentiation, apoptosis, and development. In unstimulated cells, NF-κB/Rel proteins are sequestered in the cytoplasm by IκB inhibitor proteins. Many extracellular stimuli, such as tumor necrosis factor α (TNFα), cause rapid phosphorylation of IκB at N-terminal serine residues leading to ubiquitination and degradation of the inhibitor. Subsequently, NF-κB proteins translocate to the nucleus and activate gene expression through κB response elements. TNFα, as well as certain other stimuli, also induces the phosphorylation of the NF-κB proteins. Previously, we have shown that TNFα induces RelA/p65 phosphorylation at serine 529 and that this inducible phosphorylation increases NF-κB transcriptional activity on an exogenously supplied reporter (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). In this report, we demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFα-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IκBα and p65 inhibits p65 phosphorylation by CKII and that degradation of IκBα allows CKII to phosphorylate p65 to increase NF-κB transactivation potential. These data may explain the ability of CKII to modulate cell growth and demonstrate a mechanism whereby CKII can function in an inducible manner. nuclear factor κB Rel homology domain inhibitor of κB, TNFα, tumor necrosis factor α IκB kinase casein kinase II protein kinase A lipopolysaccharide polyacrylamide gel electrophoresis CREB binding protein The NF-κB1/Rel transcription factors play critical roles in regulating the expression of a variety of genes involved in immune and inflammatory responses, cell proliferation, and apoptosis (2Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5592) Google Scholar, 3Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4631) Google Scholar). NF-κB was first identified as a constitutively active transcription factor that binds to the immunoglobulin κ light chain enhancer in mature B cells (4Sen R. Baltimore D. Cell. 1986; 46: 705-716Abstract Full Text PDF PubMed Scopus (1946) Google Scholar). There are five members of the mammalian Rel family of proteins that have been cloned and characterized: RelA/p65, c-Rel, NF-κB1 (p50/p105), NF-κB2 (p52/p100), and RelB (2Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5592) Google Scholar, 3Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4631) Google Scholar, 5Baeuerle P.A. Henkel T. Annu. Rev. Immunol. 1994; 12: 141-179Crossref PubMed Scopus (4602) Google Scholar). Each of these proteins is characterized by a Rel homology domain (RHD), which is involved in dimerization, DNA binding, interactions with IκB, and nuclear localization. Several, but not all, of the NF-κB proteins contain transcriptional activation domains, which promote interactions with basal transcription components or with transcriptional co-activators. For example, RelA/p65 contains at least two transactivation domains in the C-terminal region and an element in the RHD involved with recruitment of co-activators (2Baldwin Jr., A.S. Annu. Rev. Immunol. 1996; 14: 649-683Crossref PubMed Scopus (5592) Google Scholar, 3Ghosh S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4631) Google Scholar, 6Zhong H. SuYang H. Erdjument-Bromage H. Tempst P. Ghosh S. Cell. 1997; 89: 413-424Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar). In most unstimulated cells, NF-κB is sequestered in the cytoplasm by IκB proteins that mask the nuclear localization sequence of NF-κB (7Ganchi P.A. Sun S.C. Greene W.C. Ballard D.W. Mol. Biol. Cell. 1992; 3: 1339-1352Crossref PubMed Scopus (204) Google Scholar, 8Beg A.A. 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Regarding the latter point, NF-κB is now known to regulate transcription of cyclin D1 and c-Myc, to be activated by a variety of oncoproteins, and to be required for oncogenesis or tumorigenesis in different settings (17Mayo M.W. Baldwin Jr., A.S. Rev. Cancer Online. 2000; 1470: M55-M62Google Scholar). Interestingly, nuclear translocation and DNA binding are apparently not sufficient to activate an NF-κB-dependent reporter. For example, it has been shown that inhibition of tyrosine kinase signaling inhibits the ability of interleukin-1 to activate an NF-κB-dependent reporter but does not block nuclear translocation and DNA binding of NF-κB (18Yoza B.K. Hu J.Y.Q. McCall C.E. J. Biol. Chem. 1996; 271: 18306-18309Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar). 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Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). we have that TNFα of and cells leads to phosphorylation of p65 on serine which leads to transcriptional potential (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). Interestingly, the sequence serine 529 the for casein kinase II (CKII) CKII is a which is to D.W. Mol. Cell. Biochem. 1993; PubMed Scopus Google Scholar). In most CKII is a of two α and two J.A. 1991; Google Scholar, PubMed Scopus Google Scholar). of genes α and of CKII in results in a of cell R. Mol. Cell. Biol. PubMed Scopus Google that CKII is The sequence for CKII phosphorylation is serine the be or D.W. Mol. Cell. Biochem. 1993; PubMed Scopus Google Scholar). proteins have been found to be of transcription of transcription factors by CKII can affect nuclear DNA binding, or transactivation D.W. Mol. Cell. Biochem. 1993; PubMed Scopus Google Scholar). For example, phosphorylation of by CKII DNA binding ability A. J. T. T. N. U. T. D. Karin M. Cell. 1992; Full Text PDF PubMed Scopus Google phosphorylation by CKII with transcription to activate transcription J.M. C. S. M.J. M.L. Science. 1993; PubMed Scopus Google Scholar). it has been shown that of CKII enhances cell G. R. D.W. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar) and tumor in a E. 1998; 16: PubMed Scopus Google evidence for a for CKII in oncogenesis and cell CKII has been to regulate NF-κB activity through of have that CKII constitutively the C-terminal region of IκBα U. S. A. 1995; PubMed Scopus Google Scholar, R. P. C. S. J. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, J.A. N. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, D. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar). was that this phosphorylation is required for the basal of the IκBα protein R. P. C. S. J. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, D. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar). found that the C-terminal region of IκBα is for degradation D. Scheidereit C. EMBO J. 1996; PubMed Scopus Google Scholar). CKII also inducible phosphorylation of it was found that CKII serine of IκBα in response to TNFα or of cells. to phosphorylation of RelA/p65, et al. K. Dower S.K. H. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) have that a kinase with with CKII activity with RelA/p65 in and cells and that CKII can phosphorylate p65 in vitro. In this we that CKII p65 at serine 529 following TNFα CKII activity is in cells. evidence in unstimulated cells, the association of IκBα with NF-κB inhibits CKII phosphorylation of degradation of IκBα this inhibition and CKII to phosphorylate p65 on serine These results a to explain the of CKII with oncogenesis and cell and a mechanism to explain inducible CKII cells and the cells that or (1Wang D. Baldwin Jr., A.S. J. Biol. 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J. 1997; PubMed Scopus Google Scholar). was by the chain the of B The for the chain is The are and p65 was For cells in with for and by the (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). For CKII p65 or p65 was with CKII at for in and of For PKA the proteins with PKA catalytic subunit at for in and p65 in to the and by or by for CKII cells or with TNFα for various in cell by cell to for casein kinase II activity by a casein TNFα of cells or induces phosphorylation of p65 on serine 529 (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). of the sequence of serine 529 that it is a CKII J.A. 1991; Google Scholar, PubMed Scopus Google Scholar). the sequence the for CKII was that CKII p65 in response to TNFα this we first CKII interacts with vivo. p65 was p65 that have been with p65 cells in D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google and the proteins to an The results of these that the two by the These two the CKII catalytic α and as the was these two a positive the the The in which the cell with an and the proteins by an that the p65 The data shown in A and the by et al. K. Dower S.K. H. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google that NF-κB kinase activity that was for CKII was not by this we then to TNFα of cells the between CKII and cells or with TNFα for various cell to with and the proteins by the shown in the CKII TNFα Interestingly, the between CKII and a p65 that be following TNFα that serine 529 of p65 may be a for CKII and that phosphorylation of p65 may cause the of CKII p65 at serine p65 and p65 the of cells and for in vitro kinase with shown in CKII p65 but not and that the of phosphorylation of by CKII is not to protein p65 cells can also be by CKII which has been to phosphorylate p65 (6Zhong H. SuYang H. Erdjument-Bromage H. Tempst P. Ghosh S. Cell. 1997; 89: 413-424Abstract Full Text Full Text PDF PubMed Scopus (727) Google the protein as as the p65 In p65 but not was by and this phosphorylation was inhibited by the inhibitor on PKA phosphorylation of p65 These results demonstrated that CKII p65 in vitro and that phosphorylation at serine then to CKII p65 in vivo. are in which CKII function can be inhibited in vivo by The the that CKII α and for with of not CKII of leads to of as in cells R. Mol. Cell. Biol. PubMed Scopus Google Scholar, J. R. C. Mol. Cell. Biol. PubMed Scopus Google Scholar). we a to we block TNFα-induced p65 is a which was found to expression 1996; 12: PubMed Scopus Google Scholar). The for inhibition was found to be as this interacts with the kinase at the binding J.E. U. S. A. 1997; PubMed Scopus Google Scholar). Consistent with 1996; 12: PubMed Scopus Google we found that not affect TNFα-induced NF-κB nuclear translocation and DNA binding in cells inhibited transcription of cells with TNFα-induced p65 phosphorylation These results that CKII p65 in response to TNFα in cells. to serine 529 as the of phosphorylation (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). group has that IKK can phosphorylate p65 in vivo and in vitro on serine 536 H. H. H. T. W. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In to that serine 529 is in response to TNFα we an to a with at with this of 529 following TNFα of cells it is that serine 529 is a of phosphorylation following TNFα of cells or then this to inducible phosphorylation of RelA/p65 on serine 529 such a explain CKII be associated with p65 but not phosphorylate this In to this we cells with the proteasome inhibitor and then the cells with cells to the for but shown in TNFα phosphorylation on with phosphorylation at inhibited the that IκB degradation is required for inducible and with this expression of the of IκBα the TNFα-induced phosphorylation of p65 not of CKII activity has been to There have been that CKII activity is and is not to J.A. 1991; Google Scholar, PubMed Scopus Google Scholar, T. Karin M. Cell. 1992; Full Text PDF PubMed Scopus Google Scholar). other studies that of CKII activity can in response to growth factors such as growth factor J. Biol. Chem. Full Text PDF PubMed Google Scholar) and growth factor P. N. J. Biol. Chem. Full Text PDF PubMed Google Scholar). was for to TNFα-induced p65 phosphorylation with CKII cells with TNFα for various and cells by to that may with the kinase cell then to with and CKII activity was a CKII a R. F. R. F. J. J. Biochem. 1999; PubMed Scopus Google we not to a increase in CKII activity in response to TNFα the CKII protein was and kinase activity was following TNFα In to explain the inducible activation of CKII activity to NF-κB phosphorylation and to explain the that inhibition of IκB degradation inhibited inducible we that the association of CKII with the NF-κB leads to inhibition of kinase activity IκB is our was to the in vitro CKII kinase shown in the of IκBα inhibited p65 phosphorylation by these data indicate that CKII is in the it phosphorylate of IκBα degradation to of CKII it to phosphorylate The of the of the transcription factor NF-κB that NF-κB is activated by two that to be mechanism the of NF-κB to the nucleus following of cells to a variety of This mechanism is by the activation of IKK which subsequently IκB proteins on N-terminal serine residues leading to ubiquitination and the degradation of IκB S. May M.J. Kopp E.B. Annu. Rev. Immunol. 1998; 16: 225-260Crossref PubMed Scopus (4631) Google Scholar). A well of NF-κB phosphorylation of RelA/p65 in response to a variety of Interestingly, it is that phosphorylation may be required for transcriptional function of NF-κB. Zhong et al. (6Zhong H. SuYang H. Erdjument-Bromage H. Tempst P. Ghosh S. Cell. 1997; 89: 413-424Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, H. Voll R.E. Ghosh S. Mol Cell. 1998; 1: 661-671Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar) that LPS induces phosphorylation of RelA/p65 on in B and T cells and that this phosphorylation enhances the with the transcriptional co-activators CBP and The phosphorylation of is by the catalytic subunit of PKA associated with the NF-κB to the for phosphorylation of p65 by it is that degradation of IκB allows the PKA catalytic subunit to phosphorylate RelA/p65 on et al. N. Leung S. Stark G.R. Mol. Cell. Biol. 1999; 19: 4798-4805Crossref PubMed Google Scholar) that phosphorylation of p65 by interleukin-1 and and that this response the transcription function of NF-κB. Another group has data that IKK may be involved in inducible phosphorylation of p65, that IKK can phosphorylate serine vitro and in cells H. H. H. T. W. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). are data that this phosphorylation to transcriptional potential. Previously, we have shown that phosphorylation of serine 529 to the ability of p65 to activate a reporter. have provided evidence that phosphorylation of NF-κB may DNA binding, in our studies we not an of of serine 529 on DNA binding (1Wang D. Baldwin Jr., A.S. J. Biol. Chem. 1998; 273: 29411-29416Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar). have shown in this that the kinase CKII interacts with p65 in and CKII p65 at serine 529 in vitro. A CKII inhibitor TNFα-induced p65 that CKII p65 in response to TNFα in vivo. The results in this also suggest an mechanism by which the activity of CKII is data indicate that CKII is associated with the but is to phosphorylate p65 IκBα is is CKII interacts with p65 or with IκB or CKII is a and kinase which a of nuclear proteins in cell proliferation, such as and T D.W. Mol. Cell. Biochem. 1993; PubMed Scopus Google Scholar). The of CKII phosphorylation on the For example, CKII the transcriptional factor to the DNA binding activity of Genes Dev. 1992; 6: PubMed Scopus Google phosphorylation of by CKII promotes the with J.M. C. S. M.J. M.L. Science. 1993; PubMed Scopus Google Scholar). have shown that p65 is also a for CKII and phosphorylation of p65 by CKII increases NF-κB transcriptional potential. RelA/p65 has been shown to be in response to interleukin-1 and LPS J. Sims J.E. Sibley C.H. Valentine M.A. Dower S.K. Meier K.E. Bomsztyk K. J. Biol. Chem. 1991; 266: 12722-12733Abstract Full Text PDF PubMed Google and the p65 kinase that with NF-κB and IκB has a that is to the CKII α subunit T. Sekine T. Okamoto T. J. Biol. Chem. 1993; 268: 26790-26795Abstract Full Text PDF PubMed Google Scholar). et al. K. Dower S.K. H. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) demonstrated that a kinase with CKII with p65 and vitro. it has been that p65 phosphorylation by PKA at serine enhances with the transcriptional (6Zhong H. SuYang H. Erdjument-Bromage H. Tempst P. Ghosh S. Cell. 1997; 89: 413-424Abstract Full Text Full Text PDF PubMed Scopus (727) Google Scholar, H. Voll R.E. Ghosh S. Mol Cell. 1998; 1: 661-671Abstract Full Text Full Text PDF PubMed Scopus (1024) Google Scholar). different signals different phosphorylation on p65 is but may be by in cell or in has been shown that CKII IκBα at C-terminal region on serine and residues and the function of this is that the phosphorylation of the region by CKII is required for the basal of the IκBα proteins U. S. A. 1995; PubMed Scopus Google Scholar, R. P. C. S. J. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, J.A. N. Mol. Cell. Biol. 1996; 16: PubMed Google D. Scheidereit C. EMBO J. 1996; PubMed Scopus Google Scholar). CKII also the domain of X. Ballard D.W. Mol. Cell. Biol. 1996; 16: PubMed Google Scholar, K. M. D. Mol. Cell. Biol. 1997; PubMed Google which is required for to with or other NF-κB to NF-κB DNA CKII was shown to be in the kinase that IκBα at serine with and R. F. R. F. J. J. Biochem. 1999; PubMed Scopus Google Scholar) in the or cell In the in CKII serine of the serine or of the other or CKII may or with kinase to the N-terminal serine phosphorylation and degradation of IκBα in response to CKII to regulate NF-κB at two by IκBα to and by p65 to increase NF-κB transcriptional CKII has been shown to be for cell and for cell proliferation. CKII are in and in such as and and U. G. G. J. Biochem. PubMed Scopus Google Scholar). In CKII with and to P. Science. 1995; PubMed Scopus Google Scholar, M.A. P. EMBO J. 1996; PubMed Scopus Google Scholar). NF-κB also an in cell proliferation. of NF-κB have been with M. D.W. 1996; 13: Google Scholar, R. 1996; 16: Google and NF-κB has been shown to be required for by and by the D. Baldwin Jr., A.S. Genes Dev. 1998; 12: PubMed Scopus Google Scholar, A.A. Baldwin Jr., A.S. J. Biol. 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