Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation

Oncogene volume 27, pages 3789–3796 (2008)Cite this article

Abstract

Acute promyelocytic leukemia is associated with chromosomal translocations that involve the RARα gene and several distinct loci producing a variety of fusion proteins. One such fusion partner is promyelocytic leukemia zinc-finger gene (PLZF), a member of the POK (POZ and Krüppel) family of transcriptional repressors that is a key developmental regulator, stem cell maintenance factor and tumor suppressor. Overexpression of PLZF has been shown to induce cell cycle arrest at the G1 to S transition and repress the expression of key pro-proliferative genes such as CCNA2 and MYC. However, given this data suggesting an important growth inhibitory role for PLZF, relatively little is known regarding regulation of its activity. Here we show that the main cyclin-dependent kinase involved at the G1 to S transition (CDK2) phosphorylates PLZF at two consensus sites found within PEST domains present in the hinge region of the protein. This phosphorylation triggers the ubiquitination and subsequent degradation of PLZF, which impairs PLZF transcriptional repression ability and antagonizes its growth inhibitory effects. This critical mechanism of PLZF regulation may thus be relevant for cell cycle progression during the development and the pathogenesis of human cancer.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  • Barna M, Hawe N, Niswander L, Pandolfi PP . (2000). Plzf regulates limb and axial skeletal patterning. Nat Genet 25: 166–172.

    Article  CAS  Google Scholar 

  • Barna M, Merghoub T, Costoya JA, Ruggero D, Branford M, Bergia A et al. (2002). Plzf mediates transcriptional repression of HoxD gene expression through chromatin remodeling. Dev Cell 3: 499–510.

    Article  CAS  Google Scholar 

  • Bonifacino JS, Dasso M, Harford JB, Lippincott-Schwartz J, Yamada KM . (2000). Current Protocols in Cell Biology. John Wiley: Cambridge.

    Google Scholar 

  • Brissette JL, Kumar NM, Gilula NB, Dotto GP . (1991). The tumor promoter 12-O-tetradecanoylphorbol-13-acetate and the ras oncogene modulate expression and phosphorylation of gap junction proteins. Mol Cell Biol 11: 5364–5371.

    Article  CAS  Google Scholar 

  • Buaas FW, Kirsh AL, Sharma M, McLean DJ, Morris JL, Griswold MD et al. (2004). Plzf is required in adult male germ cells for stem cell self-renewal. Nat Genet 36: 647–652.

    Article  CAS  Google Scholar 

  • Chao TT, Chang CC, Shih HM . (2007). SUMO modification modulates the transrepression activity of PLZF. Biochem Biophys Res Commun 358: 475–482.

    Article  CAS  Google Scholar 

  • Chen Z, Brand NJ, Chen A, Chen SJ, Tong JH, Wang ZY et al. (1993). Fusion between a novel Kruppel-like zinc finger gene and the retinoic acid receptor-alpha locus due to a variant t(11;17) translocation associated with acute promyelocytic leukaemia. EMBO J 12: 1161–1167.

    Article  CAS  Google Scholar 

  • Cook M, Gould A, Brand N, Davies J, Strutt P, Shaknovich R et al. (1995). Expression of the zinc-finger gene PLZF at rhombomere boundaries in the vertebrate hindbrain. Proc Natl Acad Sci USA 92: 2249–2253.

    Article  CAS  Google Scholar 

  • Costoya JA, Hobbs RM, Barna M, Cattoretti G, Manova K, Sukhwani M et al. (2004). Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet 36: 653–659.

    Article  CAS  Google Scholar 

  • Costoya JA, Pandolfi PP . (2001). The role of promyelocytic leukemia zinc finger and promyelocytic leukemia in leukemogenesis and development. Curr Opin Hematol 8: 212–217.

    Article  CAS  Google Scholar 

  • Deed RW, Hara E, Atherton GT, Peters G, Norton JD . (1997). Regulation of Id3 cell cycle function by Cdk-2-dependent phosphorylation. Mol Cell Biol 17: 6815–6821.

    Article  CAS  Google Scholar 

  • Filipponi D, Hobbs RM, Ottolenghi S, Rossi P, Jannini EA, Pandolfi PP et al. (2007). Repression of kit expression by Plzf in germ cells. Mol Cell Biol 27: 6770–6781.

    Article  CAS  Google Scholar 

  • Guidez F, Howell L, Isalan M, Cebrat M, Alani RM, Ivins S et al. (2005). Histone acetyltransferase activity of p300 is required for transcriptional repression by the promyelocytic leukemia zinc finger protein. Mol Cell Biol 25: 5552–5566.

    Article  CAS  Google Scholar 

  • Hock H, Hamblen MJ, Rooke HM, Schindler JW, Saleque S, Fujiwara Y et al. (2004). Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431: 1002–1007.

    Article  CAS  Google Scholar 

  • Johnson TK, Schweppe RE, Septer J, Lewis RE . (1999). Phosphorylation of B-Myb regulates its transactivation potential and DNA binding. J Biol Chem 274: 36741–36749.

    Article  CAS  Google Scholar 

  • Kang SI, Chang WJ, Cho SG, Kim IY . (2003). Modification of promyelocytic leukemia zinc finger protein (PLZF) by SUMO-1 conjugation regulates its transcriptional repressor activity. J Biol Chem 278: 51479–51483.

    Article  CAS  Google Scholar 

  • Koff A, Cross F, Fisher A, Schumacher J, Leguellec K, Philippe M et al. (1991). Human cyclin E a new cyclin that interacts with two members of the CDC2 gene family. Cell 66: 1217–1228.

    Article  CAS  Google Scholar 

  • Li JY, English MA, Ball HJ, Yeyati PL, Waxman S, Licht JD . (1997). Sequence-specific DNA binding and transcriptional regulation by the promyelocytic leukemia zinc finger protein. J Biol Chem 272: 22447–22455.

    Article  CAS  Google Scholar 

  • Malumbres M, Barbacid M . (2001). To cycle or not to cycle: a critical decision in cancer. Nat Rev Cancer 1: 222–231.

    Article  CAS  Google Scholar 

  • Nanba D, Mammoto A, Hashimoto K, Higashiyama S . (2003). Proteolytic release of the carboxy-terminal fragment of proHB-EGF causes nuclear export of PLZF. J Cell Biol 163: 489–502.

    Article  CAS  Google Scholar 

  • Niu H, Ye BH, Dalla-Favera R . (1998). Antigen receptor signaling induces MAP kinase-mediated phosphorylation and degradation of the BCL-6 transcription factor. Genes Dev 12: 1953–1961.

    Article  CAS  Google Scholar 

  • Piazza F, Costoya JA, Merghoub T, Hobbs RM, Pandolfi PP . (2004). Disruption of PLZP in mice leads to increased T-lymphocyte proliferation cytokine production and altered hematopoietic stem cell homeostasis. Mol Cell Biol 24: 10456–10469.

    Article  CAS  Google Scholar 

  • Rechsteiner M, Rogers SW . (1996). PEST sequences and regulation by proteolysis. Trends Biochem Sci 21: 267–271.

    Article  CAS  Google Scholar 

  • Reid A, Gould A, Brand N, Cook M, Strutt P, Li J et al. (1995). Leukemia translocation gene PLZF is expressed with a speckled nuclear pattern in early hematopoietic progenitors. Blood 86: 4544–4552.

    CAS  PubMed  Google Scholar 

  • Rogatsky I, Trowbridge JM, Garabedian MJ . (1999). Potentiation of human estrogen receptor alpha transcriptional activation through phosphorylation of serines 104 and 106 by the cyclin A-CDK2 complex. J Biol Chem 274: 22296–22302.

    Article  CAS  Google Scholar 

  • Senbonmatsu T, Saito T, Landon EJ, Watanabe O, Price Jr E, Roberts RL et al. (2003). A novel angiotensin II type 2 receptor signaling pathway: possible role in cardiac hypertrophy. EMBO J 22: 6471–6482.

    Article  CAS  Google Scholar 

  • Shaknovich R, Yeyati PL, Ivins S, Melnick A, Lempert C, Waxman S et al. (1998). The promyelocytic leukemia zinc finger protein affects myeloid cell growth differentiation and apoptosis. Mol Cell Biol 18: 5533–5545.

    Article  CAS  Google Scholar 

  • Sherr CJ, Roberts JM . (1999). CDK inhibitors: positive and negative regulators of G1-phase progression. Genes Dev 13: 1501–1512.

    Article  CAS  Google Scholar 

  • Ubersax JA, Ferrell Jr JE . (2007). Mechanisms of specificity in protein phosphorylation. Nat Rev Mol Cell Biol 8: 530–541.

    Article  CAS  Google Scholar 

  • Yeyati PL, Shaknovich R, Boterashvili S, Li J, Ball HJ, Waxman S et al. (1999). Leukemia translocation protein PLZF inhibits cell growth and expression of cyclin A. Oncogene 18: 925–934.

    Article  CAS  Google Scholar 

  • Zhang J, Grindley JC, Yin T, Jayasinghe S, He XC, Ross JT et al. (2006). PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature 441: 518–522.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T Merghoub for supplying the PLZF reporter construct, E Rego, M Bhaumik and F Piazza for experimental assistance and other members of the Pandolfi lab for advice and constructive discussion. This work was supported by the NCI through grant CA-71692 to PPP and by Spanish Ministry of Education and Science (MEC) through grant SAF2005-00306 and Xunta de Galicia through grant PGIDIT05PXIB20801PR to JAC.

Author information

Author notes

  1. J A Costoya

    Present address: 2Current address: Grupo de Oncoloxía Molecular, Departamento de Fisioloxía, Facultade de Medicina, Universidade de Santiago de Compostela, Rúa San Francisco s/n, 15782 Santiago de Compostela, Spain.,

  2. R M Hobbs & P P Pandolfi

    Present address: 3Current address: Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.,

Authors and Affiliations

  1. Department of Pathology, Cancer Biology and Genetics Program, Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    J A Costoya, R M Hobbs & P P Pandolfi

Authors
  1. J A Costoya
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R M Hobbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. P P Pandolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P P Pandolfi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Costoya, J., Hobbs, R. & Pandolfi, P. Cyclin-dependent kinase antagonizes promyelocytic leukemia zinc-finger through phosphorylation. Oncogene 27, 3789–3796 (2008). https://doi.org/10.1038/onc.2008.7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.7

Keywords

This article is cited by

Search

Advanced search

Quick links