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:

Animal Models

The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling

Abstract

De-ubiquitinating enzymes (DUBs) can reverse the modifications catalyzed by ubiquitin ligases and as such are believed to be important regulators of a variety of cellular processes. Several members of this protein family have been associated with human cancers; however, there is little evidence for a direct link between deregulated de-ubiquitination and neoplastic transformation. Ubiquitin C-terminal hydrolase (UCH)-L1 is a DUB of unknown function that is overexpressed in several human cancers, but whether it has oncogenic properties has not been established. To address this issue, we generated mice that overexpress UCH-L1 under the control of a ubiquitous promoter. Here, we show that UCH-L1 transgenic mice are prone to malignancy, primarily lymphomas and lung tumors. Furthermore, UCH-L1 overexpression strongly accelerated lymphomagenesis in Eμ-myc transgenic mice. Aberrantly expressed UCH-L1 boosts signaling through the Akt pathway by downregulating the antagonistic phosphatase PHLPP1, an event that requires its de-ubiquitinase activity. These data provide the first in vivo evidence for DUB-driven oncogenesis and suggest that UCH-L1 hyperactivity deregulates normal Akt signaling.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Hoeller D, Hecker CM, Dikic I . Ubiquitin and ubiquitin-like proteins in cancer pathogenesis. Nat Rev Cancer 2006; 6: 776–788.

    Article  CAS  PubMed  Google Scholar 

  2. Glickman MH, Ciechanover A . The ubiquitin-proteasome proteolytic pathway: destruction for the sake of construction. Physiol Rev 2002; 82: 373–428.

    Article  CAS  PubMed  Google Scholar 

  3. Nijman SM, Luna-Vargas MP, Velds A, Brummelkamp TR, Dirac AM, Sixma TK et al. A genomic and functional inventory of deubiquitinating enzymes. Cell 2005; 123: 773–786.

    Article  CAS  PubMed  Google Scholar 

  4. Schmitz R, Hansmann ML, Bohle V, Martin-Subero JI, Hartmann S, Mechtersheimer G et al. TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma. J Exp Med 2009; 206: 981–989.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Novak U, Rinaldi A, Kwee I, Nandula SV, Rancoita PM, Compagno M et al. The NF-{kappa}B negative regulator TNFAIP3 (A20) is inactivated by somatic mutations and genomic deletions in marginal zone lymphomas. Blood 2009; 113: 4918–4921.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Honma K, Tsuzuki S, Nakagawa M, Tagawa H, Nakamura S, Morishima Y et al. TNFAIP3/A20 functions as a novel tumor suppressor gene in several subtypes of non-Hodgkin lymphomas. Blood 2009; 114: 2467–2475.

    Article  CAS  PubMed  Google Scholar 

  7. Compagno M, Lim WK, Grunn A, Nandula SV, Brahmachary M, Shen Q et al. Mutations of multiple genes cause deregulation of NF-kappaB in diffuse large B-cell lymphoma. Nature 2009; 459: 717–721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Oliveira AM, Perez-Atayde AR, Inwards CY, Medeiros F, Derr V, Hsi BL et al. USP6 and CDH11 oncogenes identify the neoplastic cell in primary aneurysmal bone cysts and are absent in so-called secondary aneurysmal bone cysts. Am J Pathol 2004; 165: 1773–1780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bignell GR, Warren W, Seal S, Takahashi M, Rapley E, Barfoot R et al. Identification of the familial cylindromatosis tumour-suppressor gene. Nat Genet 2000; 25: 160–165.

    Article  CAS  PubMed  Google Scholar 

  10. Hussain S, Zhang Y, Galardy PJ . DUBs and cancer: the role of deubiquitinating enzymes as oncogenes, non-oncogenes and tumor suppressors. Cell Cycle 2009; 8: 1688–1697.

    Article  CAS  PubMed  Google Scholar 

  11. Massoumi R, Chmielarska K, Hennecke K, Pfeifer A, Fassler R . Cyld inhibits tumor cell proliferation by blocking Bcl-3-dependent NF-kappaB signaling. Cell 2006; 125: 665–677.

    Article  CAS  PubMed  Google Scholar 

  12. Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K et al. Frequent inactivation of A20 in B-cell lymphomas. Nature 2009; 459: 712–716.

    Article  CAS  PubMed  Google Scholar 

  13. Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP et al. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science 2000; 289: 2350–2354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Larsen CN, Krantz BA, Wilkinson KD . Substrate specificity of deubiquitinating enzymes: ubiquitin C-terminal hydrolases. Biochemistry 1998; 37: 3358–3368.

    Article  CAS  PubMed  Google Scholar 

  15. Wilkinson KD, Lee KM, Deshpande S, Duerksen-Hughes P, Boss JM, Pohl J . The neuron-specific protein PGP 9.5 is a ubiquitin carboxyl-terminal hydrolase. Science 1989; 246: 670–673.

    Article  CAS  PubMed  Google Scholar 

  16. Liu Y, Fallon L, Lashuel HA, Liu Z, Lansbury Jr PT . The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson's disease susceptibility. Cell 2002; 111: 209–218.

    Article  CAS  PubMed  Google Scholar 

  17. Gavioli R, Frisan T, Vertuani S, Bornkamm GW, Masucci MG . c-myc overexpression activates alternative pathways for intracellular proteolysis in lymphoma cells. Nat Cell Biol 2001; 3: 283–288.

    Article  CAS  PubMed  Google Scholar 

  18. Ovaa H, Kessler BM, Rolen U, Galardy PJ, Ploegh HL, Masucci MG . Activity-based ubiquitin-specific protease (USP) profiling of virus-infected and malignant human cells. Proc Natl Acad Sci USA 2004; 101: 2253–2258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rolen U, Freda E, Xie J, Pfirrmann T, Frisan T, Masucci MG . The ubiquitin C-terminal hydrolase UCH-L1 regulates B-cell proliferation and integrin activation. J Cell Mol Med 2009; 13: 1666–1678.

    Article  PubMed  Google Scholar 

  20. Kim HJ, Kim YM, Lim S, Nam YK, Jeong J, Kim HJ et al. Ubiquitin C-terminal hydrolase-L1 is a key regulator of tumor cell invasion and metastasis. Oncogene 2009; 28: 117–127.

    Article  CAS  PubMed  Google Scholar 

  21. Bittencourt Rosas SL, Caballero OL, Dong SM, da Costa Carvalho Mda G, Sidransky D, Jen J . Methylation status in the promoter region of the human PGP9.5 gene in cancer and normal tissues. Cancer Lett 2001; 170: 73–79.

    Article  CAS  PubMed  Google Scholar 

  22. Mandelker DL, Yamashita K, Tokumaru Y, Mimori K, Howard DL, Tanaka Y et al. PGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. Cancer Res 2005; 65: 4963–4968.

    Article  CAS  PubMed  Google Scholar 

  23. Yamashita K, Park HL, Kim MS, Osada M, Tokumaru Y, Inoue H et al. PGP9.5 methylation in diffuse-type gastric cancer. Cancer Res 2006; 66: 3921–3927.

    Article  CAS  PubMed  Google Scholar 

  24. Mizukami H, Shirahata A, Goto T, Sakata M, Saito M, Ishibashi K et al. PGP9.5 methylation as a marker for metastatic colorectal cancer. Anticancer Res 2008; 28: 2697–2700.

    CAS  PubMed  Google Scholar 

  25. Liu Y, Lashuel HA, Choi S, Xing X, Case A, Ni J et al. Discovery of inhibitors that elucidate the role of UCH-L1 activity in the H1299 lung cancer cell line. Chem Biol 2003; 10: 837–846.

    Article  CAS  PubMed  Google Scholar 

  26. Luo J, Solimini NL, Elledge SJ . Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009; 136: 823–837.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Baker DJ, Perez-Terzic C, Jin F, Pitel K, Niederlander NJ, Jeganathan K et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat Cell Biol 2008; 10: 825–836.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Dietz AB, Bulur PA, Emery RL, Winters JL, Epps DE, Zubair AC et al. A novel source of viable peripheral blood mononuclear cells from leukoreduction system chambers. Transfusion 2006; 46: 2083–2089.

    Article  CAS  PubMed  Google Scholar 

  29. Novak A, Guo C, Yang W, Nagy A, Lobe CG . Z/EG, a double reporter mouse line that expresses enhanced green fluorescent protein upon Cre-mediated excision. Genesis 2000; 28: 147–155.

    Article  CAS  PubMed  Google Scholar 

  30. O'Gorman S, Dagenais NA, Qian M, Marchuk Y . Protamine-Cre recombinase transgenes efficiently recombine target sequences in the male germ line of mice, but not in embryonic stem cells. Proc Natl Acad Sci USA 1997; 94: 14602–14607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Morse III HC, Anver MR, Fredrickson TN, Haines DC, Harris AW, Harris NL et al. Bethesda proposals for classification of lymphoid neoplasms in mice. Blood 2002; 100: 246–258.

    Article  CAS  PubMed  Google Scholar 

  32. Hummel M, Bentink S, Berger H, Klapper W, Wessendorf S, Barth TF et al. A biologic definition of Burkitt's lymphoma from transcriptional and genomic profiling. N Engl J Med 2006; 354: 2419–2430.

    Article  CAS  PubMed  Google Scholar 

  33. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S et al. The c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 1985; 318: 533–538.

    Article  CAS  PubMed  Google Scholar 

  34. Harris AW, Pinkert CA, Crawford M, Langdon WY, Brinster RL, Adams JM . The E mu-myc transgenic mouse. A model for high-incidence spontaneous lymphoma and leukemia of early B cells. J Exp Med 1988; 167: 353–371.

    Article  CAS  PubMed  Google Scholar 

  35. Dalla-Favera R, Martinotti S, Gallo RC, Erikson J, Croce CM . Translocation and rearrangements of the c-myc oncogene locus in human undifferentiated B-cell lymphomas. Science 1983; 219: 963–967.

    Article  CAS  PubMed  Google Scholar 

  36. Dalla-Favera R, Bregni M, Erikson J, Patterson D, Gallo RC, Croce CM . Human c-myc onc gene is located on the region of chromosome 8 that is translocated in Burkitt lymphoma cells. Proc Natl Acad Sci USA 1982; 79: 7824–7827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Link MP, Weinstein HJ, Chapter 24. Malignant non-Hodgkin lymphomas in children. In: Pizzo PA, Poplack DG (eds). Principles and Practice of Pediatric Oncology, 5th edn. pages 722–747. Lippincott Williams & Wilkins: Philadelphia, PA, 2006.

    Google Scholar 

  38. Otsuki T, Yata K, Takata-Tomokuni A, Hyodoh F, Miura Y, Sakaguchi H et al. Expression of protein gene product 9.5 (PGP9.5)/ubiquitin-C-terminal hydrolase 1 (UCHL-1) in human myeloma cells. Br J Haematol 2004; 127: 292–298.

    Article  CAS  PubMed  Google Scholar 

  39. Ragland M, Hutter C, Zabetian C, Edwards K . Association between the ubiquitin carboxyl-terminal esterase L1 gene (UCHL1) S18Y variant and Parkinson's disease: a HuGE review and meta-analysis. Am J Epidemiol 2009; 170: 1344–1357.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Wendel HG, De Stanchina E, Fridman JS, Malina A, Ray S, Kogan S et al. Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy. Nature 2004; 428: 332–337.

    Article  CAS  PubMed  Google Scholar 

  41. Tu Y, Gardner A, Lichtenstein A . The phosphatidylinositol 3-kinase/AKT kinase pathway in multiple myeloma plasma cells: roles in cytokine-dependent survival and proliferative responses. Cancer Res 2000; 60: 6763–6770.

    CAS  PubMed  Google Scholar 

  42. Hideshima T, Nakamura N, Chauhan D, Anderson KC . Biologic sequelae of interleukin-6 induced PI3-K/Akt signaling in multiple myeloma. Oncogene 2001; 20: 5991–6000.

    Article  CAS  PubMed  Google Scholar 

  43. Andjelkovic M, Alessi DR, Meier R, Fernandez A, Lamb NJ, Frech M et al. Role of translocation in the activation and function of protein kinase B. J Biol Chem 1997; 272: 31515–31524.

    Article  CAS  PubMed  Google Scholar 

  44. Franke TF . PI3K/Akt: getting it right matters. Oncogene 2008; 27: 6473–6488.

    Article  CAS  PubMed  Google Scholar 

  45. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM . Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307: 1098–1101.

    Article  CAS  PubMed  Google Scholar 

  46. Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK et al. The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell 1995; 81: 727–736.

    Article  CAS  PubMed  Google Scholar 

  47. Beaulieu JM, Sotnikova TD, Marion S, Lefkowitz RJ, Gainetdinov RR, Caron MG . An Akt/beta-arrestin 2/PP2A signaling complex mediates dopaminergic neurotransmission and behavior. Cell 2005; 122: 261–273.

    Article  CAS  PubMed  Google Scholar 

  48. Gao T, Furnari F, Newton AC . PHLPP: a phosphatase that directly dephosphorylates Akt, promotes apoptosis, and suppresses tumor growth. Mol Cell 2005; 18: 13–24.

    Article  CAS  PubMed  Google Scholar 

  49. Maira SM, Galetic I, Brazil DP, Kaech S, Ingley E, Thelen M et al. Carboxyl-terminal modulator protein (CTMP), a negative regulator of PKB/Akt and v-Akt at the plasma membrane. Science 2001; 294: 374–380.

    Article  CAS  PubMed  Google Scholar 

  50. Li X, Liu J, Gao T . beta-TrCP-mediated ubiquitination and degradation of PHLPP1 are negatively regulated by Akt. Mol Cell Biol 2009; 29: 6192–6205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Hibi K, Westra WH, Borges M, Goodman S, Sidransky D, Jen J . PGP9.5 as a candidate tumor marker for non-small-cell lung cancer. Am J Pathol 1999; 155: 711–715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sasaki H, Yukiue H, Moriyama S, Kobayashi Y, Nakashima Y, Kaji M et al. Expression of the protein gene product 9.5, PGP9.5, is correlated with T-status in non-small cell lung cancer. Jpn J Clin Oncol 2001; 31: 532–535.

    Article  CAS  PubMed  Google Scholar 

  53. Levine PH, Kamaraju LS, Connelly RR, Berard CW, Dorfman RF, Magrath I et al. The American Burkitt's Lymphoma Registry: eight years' experience. Cancer 1982; 49: 1016–1022.

    Article  CAS  PubMed  Google Scholar 

  54. Hennessy BT, Smith DL, Ram PT, Lu Y, Mills GB . Exploiting the PI3K/AKT pathway for cancer drug discovery. Nat Rev Drug Discov 2005; 4: 988–1004.

    Article  CAS  PubMed  Google Scholar 

  55. Yoeli-Lerner M, Toker A . Akt/PKB signaling in cancer: a function in cell motility and invasion. Cell Cycle 2006; 5: 603–605.

    Article  PubMed  Google Scholar 

  56. Marsh Rde W, Rocha Lima CM, Levy DE, Mitchell EP, Rowland Jr KM, Benson III AB . A phase II trial of perifosine in locally advanced, unresectable, or metastatic pancreatic adenocarcinoma. Am J Clin Oncol 2007; 30: 26–31.

    Article  PubMed  Google Scholar 

  57. Van Ummersen L, Binger K, Volkman J, Marnocha R, Tutsch K, Kolesar J et al. A phase I trial of perifosine (NSC 639966) on a loading dose/maintenance dose schedule in patients with advanced cancer. Clin Cancer Res 2004; 10: 7450–7456.

    Article  CAS  PubMed  Google Scholar 

  58. Hideshima T, Catley L, Yasui H, Ishitsuka K, Raje N, Mitsiades C et al. Perifosine, an oral bioactive novel alkylphospholipid, inhibits Akt and induces in vitro and in vivo cytotoxicity in human multiple myeloma cells. Blood 2006; 107: 4053–4062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu J, Weiss HL, Rychahou P, Jackson LN, Evers BM, Gao T . Loss of PHLPP expression in colon cancer: role in proliferation and tumorigenesis. Oncogene 2009; 28: 994–1004.

    Article  CAS  PubMed  Google Scholar 

  60. Hay N . The Akt-mTOR tango and its relevance to cancer. Cancer Cell 2005; 8: 179–183.

    Article  CAS  PubMed  Google Scholar 

  61. Ardley HC, Scott GB, Rose SA, Tan NG, Robinson PA . UCH-L1 aggresome formation in response to proteasome impairment indicates a role in inclusion formation in Parkinson's disease. J Neurochem 2004; 90: 379–391.

    Article  CAS  PubMed  Google Scholar 

  62. Korolchuk VI, Mansilla A, Menzies FM, Rubinsztein DC . Autophagy inhibition compromises degradation of ubiquitin-proteasome pathway substrates. Mol Cell 2009; 33: 517–527.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ying Zhang and members of the van Deursen lab for helpful discussions. We are grateful to Rick Bram, Mitchell Cairo, Andre Catic and Victor Quesada for critically reading the manuscript, as well as Drs Fang Jin and Darren Baker for their help with histopathology. PJG is a Harriet H Samuelsson Foundation Pediatric Research Cancer Scientist, is a Basic Science Scholar of the American Society of Hematology, is supported by the Howard Hughes Medical Institute Early-Career Physician Scientist Award, and is a GAFCR research fellow. JvD is supported by the NIH.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P J Galardy.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hussain, S., Foreman, O., Perkins, S. et al. The de-ubiquitinase UCH-L1 is an oncogene that drives the development of lymphoma in vivo by deregulating PHLPP1 and Akt signaling. Leukemia 24, 1641–1655 (2010). https://doi.org/10.1038/leu.2010.138

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2010.138

Keywords

This article is cited by

Search

Quick links