Abstract
Protein kinase CK2 has many established in vitro substrates, but it is only within the past few years that we have begun to ascertain which of these are its real physiological targets, how their phosphorylation may contribute towards regulating normal cell physiology, and how phosphorylation of these proteins might influence the development of diseases such as cancer. One of the well-characterised in vitro substrates for CK2 is the tumour suppressor protein, p53. However, the physiological nature of this interaction has never been fully established. In the present article, we summarise a recent study from our laboratory showing that phosphorylation of p53 at Ser392, the sole site modified by CK2 in vitro, is regulated by a novel mechanism where the stoichiometry of phosphorylation is governed by the rate of turnover of the p53 protein. Such a model is entirely consistent with phosphorylation by a constitutively active protein kinase such as CK2. In contrast to this, while there is overwhelming evidence that CK2 phosphorylates p53 in vitro and is the only detectable Ser392 protein kinase in cell extracts, our data raise uncertainty as to whether this interaction truly reflects events underpinning Ser392 phosphorylation in vivo. We consider the possible role of CK2 in regulating the p53 response in a wider context and suggest key issues that should be addressed experimentally to provide a more cohesive picture of the relationship between this important protein kinase and a pivotal anti-cancer surveillance system in cells.
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References
Riley T, Sontag E, Chen P, Levine A (2008) Transcriptional control of human p53-regulated genes. Nat Rev Mol Cell Biol 9:402–412
Vousden KH, Lane DP (2007) p53 in health and disease. Nat Rev Mol Cell Biol 8:275–283
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137:413–431
Litchfield DW (2003) Protein kinase CK2: structure, regulation and role in cellular decisions of life and death. Biochem J 369:1–15
Ruzzene M, Pinna LA (2010) Addiction to protein kinase CK2: a common denominator of diverse cancer cells? Biochim Biophys Acta 1804:499–504
Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, Bliesath J, Omori M, Huser N, Ho C, Proffitt C, Schwaebe MK, Ryckman DM, Rice WG, Anderes K (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70:10288–10298
Meggio F, Pinna LA (2003) One thousand and one substrates of protein kinase CK2? FASEB J 17:349–368
Kato T Jr, Delhase M, Hoffmann A, Karin M (2003) CK2 is a C-terminal IkappaB kinase responsible for NF-kappaB activation during the UV response. Mol Cell 12:829–839
Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H, Goodman R, Lozano G, Zhao Y, Lu H (2001) A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell 7:283–292
Anderson CW, Appella E (2009) Signaling to the p53 tumor suppressor through pathways activated by genotoxic and non-genotoxic stresses. In: Bradshaw RA, Dennis EA (eds) Handbook of cell signaling. Elsevier, Amsterdam, pp 237–247
Brooks CL, Gu W (2003) Ubiquitination, phosphorylation and acetylation: the molecular basis for p53 regulation. Curr Opin Cell Biol 15:164–171
Kruse JP, Gu W (2008) SnapShot: p53 posttranslational modifications. Cell 133:930–30 e1
Meek DW, Anderson CW (2009) Posttranslational modification of p53: cooperative integrators of function. Cold Spring Harb Perspect Biol 1:a000950
Herrmann CP, Kraiss S, Montenarh M (1991) Association of casein kinase II with immunopurified p53. Oncogene 6:877–884
Meek DW, Simon S, Kikkawa U, Eckhart W (1990) The p53 tumour suppressor protein is phosphorylated at serine 389 by casein kinase 2. EMBO J 9:3253–3260
Prowald A, Schuster N, Montenarh M (1997) Regulation of the DNA binding of p53 by its interaction with protein kinase CK2. FEBS Lett 408:99–104
Schuster N, Prowald A, Schneider E, Scheidtmann KH, Montenarh M (1999) Regulation of p53 mediated transactivation by the beta-subunit of protein kinase CK2. FEBS Lett 447:160–166
Schuster N, Gotz C, Faust M, Schneider E, Prowald A, Jungbluth A, Montenarh M (2001) Wild-type p53 inhibits protein kinase CK2 activity. J Cell Biochem 81:172–183
Hupp TR, Meek DW, Midgley CA, Lane DP (1992) Regulation of the specific DNA binding function of p53. Cell 71:875–886
Sakaguchi K, Sakamoto M, Lewis MS, Anderson CW, Erikson JW, Appella E, Xie D (1997) Phosphorylation of serine 392 stabilises the tetramer formation of tumor suppressor protein p53. Biochemistry 36:10117–10124
Milne DM, Palmer RH, Meek DW (1992) Mutation of the casein kinase II phosphorylation site abolishes the anti-proliferative activity of p53. Nucleic Acids Res 20:5565–5570
Bruins W, Zwart E, Attardi LD, Iwakuma T, Hoogervorst EM, Beems RB, Miranda B, van Oostrom CT, van den Berg J, van den Aardweg GJ, Lozano G, van Steeg H, Jacks T, de Vries A (2004) Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24:8884–8894
Hoogervorst EM, Bruins W, Zwart E, van Oostrom CT, van den Aardweg GJ, Beems RB, van den Berg J, Jacks T, van Steeg H, de Vries A (2005) Lack of p53 Ser389 phosphorylation predisposes mice to develop 2-acetylaminofluorene-induced bladder tumors but not ionizing radiation-induced lymphomas. Cancer Res 65:3610–3616
Bruins W, Bruning O, Jonker MJ, Zwart E, van der Hoeven TV, Pennings JL, Rauwerda H, de Vries A, Breit TM (2008) The absence of Ser389 phosphorylation in p53 affects the basal gene expression level of many p53-dependent genes and alters the biphasic response to UV exposure in mouse embryonic fibroblasts. Mol Cell Biol 28:1974–1987
Gillotin S, Yap D, Lu X (2010) Mutation at Ser392 specifically sensitizes mutant p53H175 to mdm2-mediated degradation. Cell Cycle 9:1390–1398
Brosh R, Rotter V (2009) When mutants gain new powers: news from the mutant p53 field. Nat Rev Cancer 9:701–713
Huang C, Ma WY, Maxiner A, Sun Y, Dong Z (1999) p38 kinase mediates UV-induced phosphorylation of p53 protein at serine 389. J Biol Chem 274:12229–12235
Keller D, Zeng X, Li X, Kapoor M, Iordanov MS, Taya Y, Lozano G, Magun B, Lu H (1999) The p38MAPK inhibitor SB203580 alleviates ultraviolet-induced phosphorylation at serine 389 but not serine 15 and activation of p53. Biochem Biophys Res Commun 261:464–471
Cuddihy AR, Wong AH, Tam NW, Li S, Koromilas AE (1999) The double-stranded RNA activated protein kinase PKR physically associates with the tumor suppressor p53 protein and phosphorylates human p53 on serine 392 in vitro. Oncogene 18:2690–2702
Radhakrishnan SK, Gartel AL (2006) CDK9 phosphorylates p53 on serine residues 33, 315 and 392. Cell Cycle 5:519–521
Claudio PP, Cui J, Ghafouri M, Mariano C, White MK, Safak M, Sheffield JB, Giordano A, Khalili K, Amini S, Sawaya BE (2006) Cdk9 phosphorylates p53 on serine 392 independently of CKII. J Cell Physiol 208:602–612
Blaydes JP, Hupp TR (1998) DNA damage triggers DRB-resistant phosphorylation of human p53 at the CK2 site. Oncogene 17:1045–1052
Kapoor M, Lozano G (1998) Functional activation of p53 via phosphorylation following DNA damage by UV but not gamma radiation. Proc Natl Acad Sci USA 95:2834–2837
Lu H, Taya Y, Ikeda M, Levine AJ (1998) Ultraviolet radiation, but not gamma radiation or etoposide-induced DNA damage, results in the phosphorylation of the murine p53 protein ar serine-389. Proc Natl Acad Sci USA 95:6399–6402
Saito S, Yamaguchi H, Higashimoto Y, Chao C, Xu Y, Fornace AJ Jr, Appella E, Anderson CW (2003) Phosphorylation site interdependence of human p53 post-translational modifications in response to stress. J Biol Chem 278:37536–37544
Saito S, Goodarzi AA, Higashimoto Y, Noda Y, Lees-Miller SP, Appella E, Anderson CW (2002) ATM mediates phosphorylation at multiple p53 sites, including Ser(46), in response to ionizing radiation. J Biol Chem 277:12491–12494
Cox ML, Meek DW (2010) Phosphorylation of serine 392 in p53 is a common and integral event during p53 induction by diverse stimuli. Cell Signal 22:564–571
de Stanchina E, McCurrach ME, Zindy F, Shieh S-Y, Ferbeyre G, Samuelson AV, Prives C, Roussel MF, Sherr CJ, Lowe SW (1998) E1A signaling to p53 involves the p19ARF tumor suppressor. Genes Dev 12:2434–2442
Thompson T, Tovar C, Yang H, Carvajal D, Vu BT, Xu Q, Wahl GM, Heimbrook DC, Vassilev LT (2004) Phosphorylation of p53 on key serines is dispensable for transcriptional activation and apoptosis. J Biol Chem 279:53015–53022
Samad A, Anderson CW, Carroll RB (1986) Mapping of phosphomonoester and apparent phosphodiester bonds of the oncogene product p53 from simian virus 40-transformed 3T3 cells. Proc Natl Acad Sci USA 83:897–901
Sayed M, Kim SO, Salh BS, Issinger OG, Pelech SL (2000) Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. J Biol Chem 275:16569–16573
Oster B, Bundgaard B, Hupp TR, Hollsberg P (2008) Human herpesvirus 6B induces phosphorylation of p53 in its regulatory domain by a CK2- and p38-independent pathway. J Gen Virol 89:87–96
McKendrick L, Milne D, Meek D (1999) Protein kinase CK2-dependent regulation of p53 function: evidence that the phosphorylation status of the serine 386 (CK2) site of p53 is constitutive and stable. Mol Cell Biochem 191:187–199
Gotz C, Kartarius S, Scholtes P, Nastainczyk W, Montenarh M (1999) Identification of a CK2 phosphorylation site in mdm2. Eur J Biochem 266:493–501
Blattner C, Hay TJ, Meek DW, Lane DP (2002) Hypophosphorylation of Mdm2 augments p53 stability. Mol Cell Biol 22:6170–6182
Huart AS, MacLaine NJ, Meek DW, Hupp TR (2009) CK1alpha plays a central role in mediating MDM2 control of p53 and E2F-1 protein stability. J Biol Chem 284:32384–32394
Kulikov R, Boehme KA, Blattner C (2005) Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance. Mol Cell Biol 25:7170–7180
Meek DW, Hupp TR (2009) The regulation of MDM2 by multisite phosphorylation—opportunities for molecular-based intervention to target tumours? Semin Cancer Biol 20:19–28
Winter M, Milne D, Dias S, Kulikov R, Knippschild U, Blattner C, Meek D (2004) Protein kinase CK1-delta phosphorylates key sites in the acidic domain of Mdm2 that regulate p53 turnover. Biochemistry 43:16356–16364
Onel K, Cordon-Cardo C (2004) MDM2 and prognosis. Mol Cancer Res 2:1–8
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The authors are grateful to the Association for International Cancer Research who funded the study described in this article.
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Meek, D.W., Cox, M. Induction and activation of the p53 pathway: a role for the protein kinase CK2?. Mol Cell Biochem 356, 133–138 (2011). https://doi.org/10.1007/s11010-011-0966-3
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DOI: https://doi.org/10.1007/s11010-011-0966-3