Molecular and Cellular Biochemistry

, Volume 316, Issue 1–2, pp 149–154 | Cite as

CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor

  • P. P. Scaglioni
  • T. M. Yung
  • S. C. Choi
  • C. Baldini
  • G. Konstantinidou
  • P. P. Pandolfi
Article

Abstract

The PML tumor suppressor controls growth suppression, induction of apoptosis, and cellular senescence. PML loss occurs frequently in hematopoietic and solid tumors. PML loss often correlates with tumor progression. Casein kinase 2 (CK2) is a stress-activated serine/threonine protein kinase that is oncogenic and frequently overexpressed in human tumor of multiple histological origins. In addition, CK2 overexpression due to gene amplification has been reported to be an adverse prognostic factor in non-small cell lung cancer. At the 5th International Conference on Protein Kinase CK2 in Padova, Italy, we reviewed our recent findings that PML undergoes ubiquitin/proteasome-mediated degradation in immortalized and tumor derived cell lines. PML degradation depends on direct CK2 phosphorylation of PML Ser517. PML mutants that are resistant to CK2 phosphorylation display increased tumor suppressive functions in assays measuring apoptosis, replicative senescence, and in xenograft models. More significantly, CK2 pharmacological inhibition enhances PML tumor suppressive property. These data identify a key post-translational mechanism that controls PML protein levels in cancer cells and suggest that CK2 inhibitors may be beneficial anti-cancer drugs.

Keywords

CK2 PML Protein polyubiquitination Lung cancer pathogenesis 

Notes

Acknowledgments

This work was supported by NIH K08 grant CA112325, ACS-IRG-02-196 award to P.P.S and NIH R01 CA71692 to PPP. P.P.S.

References

  1. 1.
    Scaglioni PP, Yung TM, Cai LF, Erdjument-Bromage H, Kaufman AJ, Singh B et al (2006) A CK2-dependent mechanism for degradation of the PML tumor suppressor. Cell 126:269–283. doi:10.1016/j.cell.2006.05.041 PubMedCrossRefGoogle Scholar
  2. 2.
    Bernardi R, Pandolfi PP (2007) Structure, dynamics and functions of promyelocytic leukaemia nuclear bodies. Nat Rev Mol Cell Biol 8:1006–1016. doi:10.1038/nrm2277 PubMedCrossRefGoogle Scholar
  3. 3.
    Matsushita H, Scaglioni PP, Bhaumik M, Rego EM, Cai LF, Majid SM et al (2006) In vivo analysis of the role of aberrant histone deacetylase recruitment and RAR alpha blockade in the pathogenesis of acute promyelocytic leukemia. J Exp Med 203:821–828. doi:10.1084/jem.20050616 PubMedCrossRefGoogle Scholar
  4. 4.
    Scaglioni PP, Pandolfi PP (2007) The theory of APL revisited. Curr Top Microbiol Immunol 313:85–100PubMedCrossRefGoogle Scholar
  5. 5.
    Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R et al (1998) PML is essential for multiple apoptotic pathways. Nat Genet 20:266–272. doi:10.1038/3030 PubMedCrossRefGoogle Scholar
  6. 6.
    Ferbeyre G, de Stanchina E, Querido E, Baptiste N, Prives C, Lowe SW (2000) PML is induced by oncogenic ras and promotes premature senescence. Genes Dev 14:2015–2027PubMedGoogle Scholar
  7. 7.
    Pearson M, Carbone R, Sebastiani C, Cioce M, Fagioli M, Saito S et al (2000) PML regulates p53 acetylation and premature senescence induced by oncogenic Ras. Nature 406:207–210. doi:10.1038/35021000 PubMedCrossRefGoogle Scholar
  8. 8.
    Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PP (2005) The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105:3686–3690. doi:10.1182/blood-2004-09-3782 PubMedCrossRefGoogle Scholar
  9. 9.
    Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP (2006) Identification of a tumor suppressor network opposing nuclear Akt function. Nature 441:523–527. doi:10.1038/nature04809 PubMedCrossRefGoogle Scholar
  10. 10.
    Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K et al (2000) Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 19:6185–6195. doi:10.1093/emboj/19.22.6185 PubMedCrossRefGoogle Scholar
  11. 11.
    Bernardi R, Guernah I, Jin D, Grisendi S, Alimonti A, Teruya-Feldstein J et al (2006) PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. Nature 442:779–785. doi:10.1038/nature05029 PubMedCrossRefGoogle Scholar
  12. 12.
    Lin HK, Bergmann S, Pandolfi PP (2004) Cytoplasmic PML function in TGF-beta signalling. Nature 431:205–211. doi:10.1038/nature02783 PubMedCrossRefGoogle Scholar
  13. 13.
    Pinna LA (2002) Protein kinase CK2: a challenge to canons. J Cell Sci 115:3873–3878. doi:10.1242/jcs.00074 PubMedCrossRefGoogle Scholar
  14. 14.
    Ahmed K, Gerber DA, Cochet C (2002) Joining the cell survival squad: an emerging role for protein kinase CK2. Trends Cell Biol 12:226–230. doi:10.1016/S0962-8924(02)02279-1 PubMedCrossRefGoogle Scholar
  15. 15.
    Buchou T, Vernet M, Blond O, Jensen HH, Pointu H, Olsen BB et al (2003) Disruption of the regulatory beta subunit of protein kinase CK2 in mice leads to a cell-autonomous defect and early embryonic lethality. Mol Cell Biol 23:908–915. doi:10.1128/MCB.23.3.908-915.2003 PubMedCrossRefGoogle Scholar
  16. 16.
    Padmanabha R, Chen-Wu JL, Hanna DE, Glover CV (1990) Isolation, sequencing, and disruption of the yeast CKA2 gene: casein kinase II is essential for viability in Saccharomyces cerevisiae. Mol Cell Biol 10:4089–4099PubMedGoogle Scholar
  17. 17.
    Fraser AG, Kamath RS, Zipperlen P, Martinez-Campos M, Sohrmann M, Ahringer J (2000) Functional genomic analysis of C elegans chromosome I by systematic RNA interference. Nature 408:325–330. doi:10.1038/35042517 PubMedCrossRefGoogle Scholar
  18. 18.
    O-charoenrat P, Rusch V, Talbot SG, Sarkaria I, Viale A, Socci N, Ngai I, Rao P, Singh B (2004) Casein kinase II alpha subunit and C1-inhibitor are independent predictors of outcome in patients with squamous cell carcinoma of the lung. Clin Cancer Res 10:5792–5803. doi:10.1158/1078-0432.CCR-03-0317 PubMedCrossRefGoogle Scholar
  19. 19.
    Landesman-Bollag E, Romieu-Mourez R, Song DH, Sonenshein GE, Cardiff RD, Seldin DC (2001) Protein kinase CK2 in mammary gland tumorigenesis. Oncogene 20:3247–3257. doi:10.1038/sj.onc.1204411 PubMedCrossRefGoogle Scholar
  20. 20.
    Seldin DC, Leder P (1995) Casein kinase II alpha transgene-induced murine lymphoma: relation to theileriosis in cattle. Science 267:894–897. doi:10.1126/science.7846532 PubMedCrossRefGoogle Scholar
  21. 21.
    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. doi:10.1016/S1097-2765(03)00358-7 PubMedCrossRefGoogle Scholar
  22. 22.
    Di Maira G, Salvi M, Arrigoni G, Marin O, Sarno S, Brustolon F et al (2005) Protein kinase CK2 phosphorylates and upregulates Akt/PKB. Cell Death Differ 12:668–677. doi:10.1038/sj.cdd.4401604 PubMedCrossRefGoogle Scholar
  23. 23.
    Song DH, Sussman DJ, Seldin DC (2000) Endogenous protein kinase CK2 participates in Wnt signaling in mammary epithelial cells. J Biol Chem 275:23790–23797. doi:10.1074/jbc.M909107199 PubMedCrossRefGoogle Scholar
  24. 24.
    Desagher S, Osen-Sand A, Montessuit S, Magnenat E, Vilbois F, Hochmann A et al (2001) Phosphorylation of bid by casein kinases I and II regulates its cleavage by caspase 8. Mol Cell 8:601–611. doi:10.1016/S1097-2765(01)00335-5 PubMedCrossRefGoogle Scholar
  25. 25.
    Gurrieri C, Capodieci P, Bernardi R, Scaglioni PP, Nafa K, Rush LJ et al (2004) Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J Natl Cancer Inst 96:269–279PubMedCrossRefGoogle Scholar
  26. 26.
    Koken MH, Linares-Cruz G, Quignon F, Viron A, Chelbi-Alix MK, Sobczak-Thepot J, Juhlin L, Degos L, Calvo F, de The H (1995) The PML growth-suppressor has an altered expression in human oncogenesis. Oncogene 10:1315–1324PubMedGoogle Scholar
  27. 27.
    Zhang P, Chin W, Chow LT, Chan AS, Yim AP, Leung SF et al (2000) Lack of expression for the suppressor PML in human small cell lung carcinoma. Int J Cancer 85:599–605. doi :10.1002/(SICI)1097-0215(20000301)85:5<599::AID-IJC1>3.0.CO;2-#PubMedCrossRefGoogle Scholar
  28. 28.
    Meggio F, Marchiori F, Borin G, Chessa G, Pinna LA (1984) Synthetic peptides including acidic clusters as substrates and inhibitors of rat liver casein kinase TS (type-2). J Biol Chem 259:14576–14579PubMedGoogle Scholar
  29. 29.
    Meggio F, Pinna LA (2003) One-thousand-and-one substrates of protein kinase CK2? FASEB J 17:349–368. doi:10.1096/fj.02-0473rev PubMedCrossRefGoogle Scholar
  30. 30.
    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. doi:10.1074/jbc.M000312200 PubMedCrossRefGoogle Scholar
  31. 31.
    Yamada M, Katsuma S, Adachi T, Hirasawa A, Shiojima S, Kadowaki T et al (2005) Inhibition of protein kinase CK2 prevents the progression of glomerulonephritis. Proc Natl Acad Sci USA 102:7736–7741. doi:10.1073/pnas.0409818102 PubMedCrossRefGoogle Scholar
  32. 32.
    Keller DM, Zeng X, Wang Y, Zhang QH, Kapoor M, Shu H et al (2001) A DNA damage-induced p53 serine 392 kinase complex contains CK2, hSpt16, and SSRP1. Mol Cell 7:283–292. doi:10.1016/S1097-2765(01)00176-9 PubMedCrossRefGoogle Scholar
  33. 33.
    Hupp TR, Meek DW, Midgley CA, Lane DP (1992) Regulation of the specific DNA binding function of p53. Cell 71:875–886. doi:10.1016/0092-8674(92)90562-Q PubMedCrossRefGoogle Scholar
  34. 34.
    Bruins W, Zwart E, Attardi LD, Iwakuma T, Hoogervorst EM, Beems RB et al (2004) Increased sensitivity to UV radiation in mice with a p53 point mutation at Ser389. Mol Cell Biol 24:8884–8894. doi:10.1128/MCB.24.20.8884-8894.2004 PubMedCrossRefGoogle Scholar
  35. 35.
    Schuster N, Gotz C, Faust M, Schneider E, Prowald A, Jungbluth A et al (2001) Wild-type p53 inhibits protein kinase CK2 activity. J Cell Biochem 81:172–183. doi :10.1002/1097-4644(20010401)81:1<172::AID-JCB1033>3.0.CO;2-OPubMedCrossRefGoogle Scholar
  36. 36.
    Roux PP, Blenis J (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev 68:320–344. doi:10.1128/MMBR.68.2.320-344.2004 PubMedCrossRefGoogle Scholar
  37. 37.
    Esteva FJ, Sahin AA, Smith TL, Yang Y, Pusztai L, Nahta R et al (2004) Prognostic significance of phosphorylated P38 mitogen-activated protein kinase and HER-2 expression in lymph node-positive breast carcinoma. Cancer 100:499–506. doi:10.1002/cncr.11940 PubMedCrossRefGoogle Scholar
  38. 38.
    Elenitoba-Johnson KS, Jenson SD, Abbott RT, Palais RA, Bohling SD, Lin Z et al (2003) Involvement of multiple signaling pathways in follicular lymphoma transformation: p38-mitogen-activated protein kinase as a target for therapy. Proc Natl Acad Sci USA 100:7259–7264. doi:10.1073/pnas.1137463100 PubMedCrossRefGoogle Scholar
  39. 39.
    Hildesheim J, Awwad RT, Fornace AJ Jr (2004) p38 Mitogen-activated protein kinase inhibitor protects the epidermis against the acute damaging effects of ultraviolet irradiation by blocking apoptosis and inflammatory responses. J Invest Dermatol 122:497–502. doi:10.1111/j.1523-1747.2004.22229.x PubMedCrossRefGoogle Scholar
  40. 40.
    Richardson PG, Barlogie B, Berenson J, Singhal S, Jagannath S, Irwin D et al (2003) A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617. doi:10.1056/NEJMoa030288 PubMedCrossRefGoogle Scholar
  41. 41.
    Mitchell BS (2003) The proteasome–an emerging therapeutic target in cancer. N Engl J Med 348:2597–2598. doi:10.1056/NEJMp030092 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2008

Authors and Affiliations

  • P. P. Scaglioni
    • 1
  • T. M. Yung
    • 2
  • S. C. Choi
    • 1
  • C. Baldini
    • 1
  • G. Konstantinidou
    • 1
  • P. P. Pandolfi
    • 3
    • 4
  1. 1.Division of Hematology-OncologyUniversity of Texas Southwestern Medical CenterDallasUSA
  2. 2.Cancer Biology and Genetics Program, Sloan-Kettering InstituteMemorial Sloan-Kettering Cancer CenterNew YorkUSA
  3. 3.Cancer Genetics Program, Beth Israel Deaconess Cancer CenterHarvard Medical SchoolBostonUSA
  4. 4.Department of Medicine, Beth Israel Deaconess Medical CenterHarvard Medical SchoolBostonUSA

Personalised recommendations