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.

Role of the proto-oncogene Pokemon in cellular transformation and ARF repression

Nature volume 433, pages 278–285 (2005)Cite this article

Abstract

Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention.

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

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

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

Figure 1: Pokemon is indispensable for cellular transformation and acts as a proto-oncogene.
Figure 2: Pokemon is a key ARF transcriptional repressor.
Figure 3: p19Arf loss reverts premature senescence and refractoriness to oncogenic transformation in Zbtb7-/- MEFs.
Figure 4: Pokemon transgenic mice develop pre-T LBL.
Figure 5: Cooperative roles of Pokemon and BCL6 in lymphomagenesis.

References

  1. Lin, R. J. et al. Role of the histone deacetylase complex in acute promyelocytic leukaemia. Nature 391, 811–814 (1998)

    Article  ADS  CAS  Google Scholar 

  2. Melnick, A. et al. Critical residues within the BTB domain of PLZF and Bcl-6 modulate interaction with corepressors. Mol. Cell. Biol. 22, 1804–1818 (2002)

    Article  CAS  Google Scholar 

  3. Barna, M., Hawe, N., Niswander, L. & Pandolfi, P. P. Plzf regulates limb and axial skeletal patterning. Nature Genet. 25, 166–172 (2000)

    Article  CAS  Google Scholar 

  4. Ye, B. H. et al. The BCL-6 proto-oncogene controls germinal-centre formation and Th2-type inflammation. Nature Genet. 16, 161–170 (1997)

    Article  CAS  Google Scholar 

  5. Adhikary, S. et al. Miz1 is required for early embryonic development during gastrulation. Mol. Cell. Biol. 23, 7648–7657 (2003)

    Article  CAS  Google Scholar 

  6. Carter, M. G. et al. Mice deficient in the candidate tumor suppressor gene Hic1 exhibit developmental defects of structures affected in the Miller–Dieker syndrome. Hum. Mol. Genet. 9, 413–419 (2000)

    Article  CAS  Google Scholar 

  7. Chen, W. Y. et al. Heterozygous disruption of Hic1 predisposes mice to a gender-dependent spectrum of malignant tumors. Nature Genet. 33, 197–202 (2003)

    Article  ADS  CAS  Google Scholar 

  8. Chen, Z. et al. 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 (1993)

    Article  CAS  Google Scholar 

  9. Ye, B. H. et al. Alterations of a zinc finger-encoding gene, BCL-6, in diffuse large-cell lymphoma. Science 262, 747–750 (1993)

    Article  ADS  CAS  Google Scholar 

  10. Davies, J. M. et al. Novel BTB/POZ domain zinc-finger protein, LRF, is a potential target of the LAZ-3/BCL-6 oncogene. Oncogene 18, 365–375 (1999)

    Article  CAS  Google Scholar 

  11. Kukita, A. et al. Osteoclast-derived zinc finger (OCZF) protein with POZ domain, a possible transcriptional repressor, is involved in osteoclastogenesis. Blood 94, 1987–1997 (1999)

    CAS  PubMed  Google Scholar 

  12. Pessler, F., Pendergrast, P. S. & Hernandez, N. Purification and characterization of FBI-1, a cellular factor that binds to the human immunodeficiency virus type 1 inducer of short transcripts. Mol. Cell. Biol. 17, 3786–3798 (1997)

    Article  CAS  Google Scholar 

  13. Weinberg, R. A. The cat and mouse games that genes, viruses, and cells play. Cell 88, 573–575 (1997)

    Article  CAS  Google Scholar 

  14. Zindy, F. et al. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev. 12, 2424–2433 (1998)

    Article  CAS  Google Scholar 

  15. Serrano, M., Lin, A. W., McCurrach, M. E., Beach, D. & Lowe, S. W. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88, 593–602 (1997)

    Article  CAS  Google Scholar 

  16. Evan, G. I. et al. Induction of apoptosis in fibroblasts by c-myc protein. Cell 69, 119–128 (1992)

    Article  CAS  Google Scholar 

  17. de Stanchina, E. et al. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev. 12,2434–2442 (1998)

    Article  CAS  Google Scholar 

  18. Wright, W. E., Binder, M. & Funk, W. Cyclic amplification and selection of targets (CASTing) for the myogenin consensus binding site. Mol. Cell. Biol. 11, 4104–4110 (1991)

    Article  CAS  Google Scholar 

  19. Bates, S. et al. p14ARF links the tumour suppressors RB and p53. Nature 395, 124–125 (1998)

    Article  ADS  CAS  Google Scholar 

  20. Rowland, B. D. et al. E2F transcriptional repressor complexes are critical downstream targets of p19(ARF)/p53-induced proliferative arrest. Cancer Cell 2, 55–65 (2002)

    Article  CAS  Google Scholar 

  21. Jacobs, J. J. L., Kieboom, K., Marino, S., DePinho, R. A. & van Lohuizen, M. The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397, 164–168 (1999)

    Article  ADS  CAS  Google Scholar 

  22. Jacobs, J. J. et al. Bmi-1 collaborates with c-Myc in tumorigenesis by inhibiting c-Myc-induced apoptosis via INK4a/ARF. Genes Dev. 13, 2678–2690 (1999)

    Article  CAS  Google Scholar 

  23. Smith, K. S. et al. Bmi-1 regulation of INK4A-ARF is a downstream requirement for transformation of hematopoietic progenitors by E2a-Pbx1. Mol. Cell 12, 393–400 (2003)

    Article  CAS  Google Scholar 

  24. Kranc, K. R. et al. Transcriptional coactivator Cited2 induces Bmi1 and Mel18 and controls fibroblast proliferation via Ink4a/ARF. Mol. Cell. Biol. 23, 7658–7666 (2003)

    Article  CAS  Google Scholar 

  25. Kim, J. H. et al. The Bmi-1 oncoprotein is overexpressed in human colorectal cancer and correlates with the reduced p16INK4a/p14ARF proteins. Cancer Lett. 203, 217–224 (2004)

    Article  CAS  Google Scholar 

  26. Vonlanthen, S. et al. The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br. J. Cancer 84, 1372–1376 (2001)

    Article  CAS  Google Scholar 

  27. Jacobs, J. J. et al. Senescence bypass screen identifies TBX2, which represses Cdkn2a (p19(ARF)) and is amplified in a subset of human breast cancers. Nature Genet. 26, 291–299 (2000)

    Article  CAS  Google Scholar 

  28. Lingbeek, M. E., Jacobs, J. J. & van Lohuizen, M. The T-box repressors TBX2 and TBX3 specifically regulate the tumor suppressor gene p14ARF via a variant T-site in the initiator. J. Biol. Chem. 277, 26120–26127 (2002)

    Article  CAS  Google Scholar 

  29. Brummelkamp, T. R. et al. TBX-3, the gene mutated in Ulnar-Mammary Syndrome, is a negative regulator of p19ARF and inhibits senescence. J. Biol. Chem. 277, 6567–6572 (2002)

    Article  CAS  Google Scholar 

  30. Inoue, K., Roussel, M. F. & Sherr, C. J. Induction of ARF tumor suppressor gene expression and cell cycle arrest by transcription factor DMP1. Proc. Natl Acad. Sci. USA 96, 3993–3998 (1999)

    Article  ADS  CAS  Google Scholar 

  31. Quelle, D. E., Zindy, F., Ashmun, R. A. & Sherr, C. J. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993–1000 (1995)

    Article  CAS  Google Scholar 

  32. Sherr, C. J. & McCormick, F. The RB and p53 pathways in cancer. Cancer Cell 2, 103–112 (2002)

    Article  CAS  Google Scholar 

  33. Lowe, S. W. & Sherr, C. J. Tumor suppression by Ink4a-Arf: progress and puzzles. Curr. Opin. Genet. Dev. 13, 77–83 (2003)

    Article  CAS  Google Scholar 

  34. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo . Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995)

    Article  ADS  CAS  Google Scholar 

  35. Iritani, B. M., Forbush, K. A., Farrar, M. A. & Perlmutter, R. M. Control of B cell development by Ras-mediated activation of Raf. EMBO J. 16, 7019–7031 (1997)

    Article  CAS  Google Scholar 

  36. Morse, H. C. III et al. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 100, 246–258 (2002)

    Article  CAS  Google Scholar 

  37. Donlon, J. A., Jaffe, E. S. & Braylan, R. C. Terminal deoxynucleotidyl transferase activity in malignant lymphomas. N. Engl. J. Med. 297, 461–464 (1977)

    Article  CAS  Google Scholar 

  38. Jaffe, E. S., Harris, N. L., Stein, H. & Vardiman, J. W. Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues (IARC Press, Lyon, France, 2001)

    Google Scholar 

  39. Whitehurst, C. E., Chattopadhyay, S. & Chen, J. Control of V(D)J recombinational accessibility of the D beta 1 gene segment at the TCR beta locus by a germline promoter. Immunity 10, 313–322 (1999)

    Article  CAS  Google Scholar 

  40. Gurrieri, C. et al. Loss of the tumor suppressor PML in human cancers of multiple histologic origins. J. Natl Cancer Inst. 96, 269–279 (2004)

    Article  CAS  Google Scholar 

  41. Alizadeh, A. A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503–511 (2000)

    Article  ADS  CAS  Google Scholar 

  42. Rosenwald, A. et al. The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 1937–1947 (2002)

    Article  Google Scholar 

  43. Hans, C. P. et al. Confirmation of the molecular classification of diffuse large B-cell lymphoma by immunohistochemistry using a tissue microarray. Blood 103, 275–282 (2004)

    Article  CAS  Google Scholar 

  44. Shvarts, A. et al. A senescence rescue screen identifies BCL6 as an inhibitor of anti-proliferative p19ARF-p53 signaling. Genes Dev. 16, 681–686 (2002)

    Article  CAS  Google Scholar 

  45. Lossos, I. S. et al. Prediction of survival in diffuse large-B-cell lymphoma based on the expression of six genes. N. Engl. J. Med. 350, 1828–1837 (2004)

    Article  CAS  Google Scholar 

  46. Sanchez-Beato, M., Sanchez-Aguilera, A. & Piris, M. A. Cell cycle deregulation in B-cell lymphomas. Blood 101, 1220–1235 (2003)

    Article  CAS  Google Scholar 

  47. Phan, R. T. & Dalla-Favera, R. The BCL6 proto-oncogene suppresses p53 expression in germinal-center B cells. Nature 432, 635–639 (2004)

    Article  ADS  CAS  Google Scholar 

  48. Carnero, A., Hudson, J. D., Price, C. M. & Beach, D. H. p16INK4A and p19ARF act in overlapping pathways in cellular immortalization. Nature Cell Biol. 2, 148–155 (2000)

    Article  CAS  Google Scholar 

  49. Hedvat, C. V. et al. Application of tissue microarray technology to the study of non-Hodgkin's and Hodgkin's lymphoma. Hum. Pathol. 33, 968–974 (2002)

    Article  Google Scholar 

Download references

Acknowledgements

We thank D. Yao, C. Hedvat, M. Dudas, J. Qin and A. Wilton for assistance on TMA preparation, staining and statistical analyses; S. Hasan for assistance with data input and management; K. Manova, C. Farrell and other Molecular Cytology Core Facility members for advice and assistance with IHC; J. Overholser and other Monoclonal Antibody Core Facility staff for help with antibody generation; G. Cattoretti and R. Dalla-Favera for advice; and L. Khandker, L. Dong, M. Hu, L. DiSantis and other P.P.P. laboratory members for assistance and discussion. This work is supported in part by an NCI grant to P.P.P.

Author information

Authors and Affiliations

  1. Cancer Biology and Genetics Program,

    Takahiro Maeda, Robin M. Hobbs, Taha Merghoub, Ilhem Guernah & Pier Paolo Pandolfi

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York, 10021, USA

    Takahiro Maeda, Robin M. Hobbs, Taha Merghoub, Ilhem Guernah, Carlos Cordon-Cardo, Julie Teruya-Feldstein & Pier Paolo Pandolfi

  3. Leukemia Research Fund Center at the Institute of Cancer Research, Chester Beatty Laboratories, Fulham Road, SW3 6JB, London, UK

    Arthur Zelent

Authors
  1. Takahiro Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robin M. Hobbs
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Taha Merghoub
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ilhem Guernah
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Arthur Zelent
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Carlos Cordon-Cardo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Julie Teruya-Feldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Pier Paolo Pandolfi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pier Paolo Pandolfi.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Supplementary information

Supplementary Figure S1

The protein expression levels of introduced oncogenes. (JPG 25 kb)

Supplementary Figure S2

Identification of Pokemon binding sequence. (JPG 65 kb)

Supplementary Figure S3

Schematic representations of the ARF promoter. (JPG 97 kb)

Supplementary Figure S4

The expression levels of Pokemon mRNA in transgenic founder lines. (JPG 29 kb)

Supplementary Figure S4

POKEMON expression in human and mouse normal lymphoid tissues. (JPG 86 kb)

Supplementary Figure S6

Kaplan-Meier curves for various prognostic markers. (JPG 75 kb)

Supplementary Tables S1 and S2

Clinical and immunohistochemical characteristics of DLBCL patients (Supplementary Table S1), and Clinical and immunohistochemical characteristics of FL patients (Supplementary Table S2). (DOC 44 kb)

Supplementary Figure Legends

Legends to accompany the above Supplementary Figures. (DOC 58 kb)

Supplementary Methods

Contains details of additional methods (retrovirus infection; real-time PCR analysis; ChIP assay; pokemon mRNA expression level in transgenic founder lines; flow cytometry analysis; immunohistochemistry for paraffin-embedded tissues; and the statistical analysis) used in this study, and an additional reference. (DOC 42 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Maeda, T., Hobbs, R., Merghoub, T. et al. Role of the proto-oncogene Pokemon in cellular transformation and ARF repression. Nature 433, 278–285 (2005). https://doi.org/10.1038/nature03203

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03203

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing