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SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability

Oncogene volume 29, pages 3044–3053 (2010)Cite this article

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Abstract

SSBP proteins bind and stabilize transcriptional cofactor LIM domain-binding protein1 (LDB1) from proteosomal degradation to promote tissue-specific transcription through an evolutionarily conserved pathway. The human SSBP2 gene was isolated as a candidate tumor suppressor from a critical region of loss in chromosome 5q14.1. By gene targeting, we show increased predisposition to B-cell lymphomas and carcinomas in Ssbp2−/− mice. Remarkably, loss of Ssbp2 causes increased LDB1 turnover in the thymus, a pathway exploited in Trp53−/−Ssbp2−/− mice to develop highly aggressive, immature thymic lymphomas. Using T-cell differentiation as a model, we report a stage-specific upregulation of Ssbp2 expression, which in turn regulates LDB1 turnover under physiological conditions. Furthermore, transcript levels of pTα, a target of LDB1-containing complex, and a critical regulator T-cell differentiation are reduced in Ssbp2−/− immature thymocytes. Our findings suggest that disruption of the SSBP2-regulated pathways may be an infrequent but critical step in malignant transformation of multiple tissues.

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References

  • Agulnick AD, Taira M, Breen JJ, Tanaka T, Dawid IB, Westphal H . (1996). Interactions of the LIM-domain-binding factor Ldb1 with LIM homeodomain proteins. Nature 384: 270–272.

    Article  CAS  PubMed  Google Scholar 

  • Aoyama M, Ozaki T, Inuzuka H, Tomotsune D, Hirato J, Okamoto Y et al. (2005). LMO3 interacts with neuronal transcription factor, HEN2, and acts as an oncogene in neuroblastoma. Cancer Res 65: 4587–4597.

    Article  CAS  PubMed  Google Scholar 

  • Bach I, Rodriguez-Esteban C, Carriere C, Bhushan A, Krones A, Rose DW et al. (1999). RLIM inhibits functional activity of LIM homeodomain transcription factors via recruitment of the histone deacetylase complex. Nat Genet 22: 394–399.

    Article  CAS  PubMed  Google Scholar 

  • Baseta JG, Stutman O . (2000). TNF regulates thymocyte production by apoptosis and proliferation of the triple negative (CD3-CD4-CD8-) subset. J Immunol 165: 5621–5630.

    Article  CAS  PubMed  Google Scholar 

  • Cai Y, Xu Z, Nagarajan L, Brandt SJ . (2008). Single-stranded DNA-binding proteins regulate the abundance and function of the LIM-homeodomain transcription factor LHX2 in pituitary cells. Biochem Biophys Res Commun 373: 303–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Capron C, Lecluse Y, Kaushik AL, Foudi A, Lacout C, Sekkai D et al. (2006). The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation. Blood 107: 4678–4686.

    Article  CAS  PubMed  Google Scholar 

  • Castro P, Liang H, Liang JC, Nagarajan L . (2002). A novel, evolutionarily conserved gene family with putative sequence-specific single-stranded DNA-binding activity. Genomics 80: 78–85.

    Article  CAS  PubMed  Google Scholar 

  • Cerretini R, Noriega MF, Narbaitz M, Slavutsky I . (2006). New chromosome abnormalities and lack of BCL-6 gene rearrangements in Argentinean diffuse large B-cell lymphomas. Eur J Haematol 76: 284–293.

    Article  PubMed  Google Scholar 

  • Chen L, Segal D, Hukriede NA, Podtelejnikov AV, Bayarsaihan D, Kennison JA et al. (2002). Ssdp proteins interact with the LIM-domain-binding protein Ldb1 to regulate development. Proc Natl Acad Sci USA 99: 14320–14325.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dave SS, Wright G, Tan B, Rosenwald A, Gascoyne RD, Chan WC et al. (2004). Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med 351: 2159–2169.

    Article  CAS  PubMed  Google Scholar 

  • Fleisig HB, Orazio NI, Liang H, Tyler AF, Adams HP, Weitzman MD et al. (2007). Adenoviral E1B55K oncoprotein sequesters candidate leukemia suppressor sequence-specific single-stranded DNA-binding protein 2 into aggresomes. Oncogene 26: 4797–4805.

    Article  CAS  PubMed  Google Scholar 

  • Goardon N, Lambert JA, Rodriguez P, Nissaire P, Herblot S, Thibault P et al. (2006). ETO2 coordinates cellular proliferation and differentiation during erythropoiesis. EMBO J 25: 357–366.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gungor C, Taniguchi-Ishigaki N, Ma H, Drung A, Tursun B, Ostendorff HP et al. (2007). Proteasomal selection of multiprotein complexes recruited by LIM homeodomain transcription factors. Proc Natl Acad Sci USA 104: 15000–15005.

    Article  PubMed  PubMed Central  Google Scholar 

  • Haines BB, Ryu CJ, Chang S, Protopopov A, Luch A, Kang YH et al. (2006). Block of T cell development in P53-deficient mice accelerates development of lymphomas with characteristic RAG-dependent cytogenetic alterations. Cancer Cell 9: 109–120.

    Article  CAS  PubMed  Google Scholar 

  • Haks MC, Krimpenfort P, van den Brakel JH, Kruisbeek AM . (1999). Pre-TCR signaling and inactivation of p53 induces crucial cell survival pathways in pre-T cells. Immunity 11: 91–101.

    Article  CAS  PubMed  Google Scholar 

  • Jacks T, Remington L, Williams BO, Schmitt EM, Halachmi S, Bronson RT et al. (1994). Tumor spectrum analysis in p53-mutant mice. Curr Biol 4: 1–7.

    Article  CAS  PubMed  Google Scholar 

  • Johnsen SA, Gungor C, Prenzel T, Riethdorf S, Riethdorf L, Taniguchi-Ishigaki N et al. (2009). Regulation of estrogen-dependent transcription by the LIM cofactors CLIM and RLIM in breast cancer. Cancer Res 69: 128–136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Koch JG, Gu X, Han Y, El-Naggar AK, Olson MV, Medina D et al. (2007). Mammary tumor modifiers in BALB/cJ mice heterozygous for p53. Mamm Genome 18: 300–309.

    Article  CAS  PubMed  Google Scholar 

  • Lecuyer E, Lariviere S, Sincennes MC, Haman A, Lahlil R, Todorova M et al. (2007). Protein stability and transcription factor complex assembly determined by the SCL-LMO2 interaction. J Biol Chem 282: 33649–33658.

    Article  CAS  PubMed  Google Scholar 

  • Liang H, Samanta S, Nagarajan L . (2005). SSBP2, a candidate tumor suppressor gene, induces growth arrest and differentiation of myeloid leukemia cells. Oncogene 24: 2625–2634.

    Article  CAS  PubMed  Google Scholar 

  • Liu JW, Nagpal JK, Sun W, Lee J, Kim MS, Ostrow KL et al. (2008). ssDNA-binding protein 2 is frequently hypermethylated and suppresses cell growth in human prostate cancer. Clin Cancer Res 14: 3754–3760.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Majeti R, Becker MW, Tian Q, Lee TL, Yan X, Liu R et al. (2009). Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc Natl Acad Sci USA 106: 3396–3401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Murre C . (2005). Helix-loop-helix proteins and lymphocyte development. Nat Immunol 6: 1079–1086.

    Article  CAS  PubMed  Google Scholar 

  • Nam CH, Rabbitts TH . (2006). The role of LMO2 in development and in T cell leukemia after chromosomal translocation or retroviral insertion. Mol Ther 13: 15–25.

    Article  CAS  PubMed  Google Scholar 

  • Natkunam Y, Farinha P, Hsi ED, Hans CP, Tibshirani R, Sehn LH et al. (2008). LMO2 protein expression predicts survival in patients with diffuse large B-cell lymphoma treated with anthracycline-based chemotherapy with and without rituximab. J Clin Oncol 26: 447–454.

    Article  CAS  PubMed  Google Scholar 

  • O'Neil J, Shank J, Cusson N, Murre C, Kelliher M. . (2004). TAL1/SCL induces leukemia by inhibiting the transcriptional activity of E47/HEB. Cancer Cell 5: 587–596.

    Article  CAS  PubMed  Google Scholar 

  • Poitras JL, Dal Cin P, Aster JC, Deangelo DJ, Morton CC . (2008). Novel SSBP2-JAK2 fusion gene resulting from a t(5;9)(q14.1;p24.1) in pre-B acute lymphocytic leukemia. Genes Chromosomes Cancer 47: 884–889.

    Article  CAS  PubMed  Google Scholar 

  • Qian Z, Fernald AA, Godley LA, Larson RA, Le Beau MM . (2002). Expression profiling of CD34+ hematopoietic stem/ progenitor cells reveals distinct subtypes of therapy-related acute myeloid leukemia. Proc Natl Acad Sci USA 99: 14925–14930.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rothenberg EV . (2007a). Cell lineage regulators in B and T cell development. Nat Immunol 8: 441–444.

    Article  CAS  PubMed  Google Scholar 

  • Rothenberg EV . (2007b). Regulatory factors for initial T lymphocyte lineage specification. Curr Opin Hematol 14: 322–329.

    Article  PubMed  Google Scholar 

  • Smith KS, Rhee JW, Naumovski L, Cleary ML . (1999). Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice. Mol Cell Biol 19: 4443–4451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sum EY, Segara D, Duscio B, Bath ML, Field AS, Sutherland RL et al. (2005). Overexpression of LMO4 induces mammary hyperplasia, promotes cell invasion, and is a predictor of poor outcome in breast cancer. Proc Natl Acad Sci USA 102: 7659–7664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tremblay M, Herblot S, Lecuyer E, Hoang T. . (2003). Regulation of pT alpha gene expression by a dosage of E2A, HEB, and SCL. J Biol Chem 278: 12680–12687.

    Article  CAS  PubMed  Google Scholar 

  • Uren AG, Kool J, Matentzoglu K, de Ridder J, Mattison J, van Uitert M . (2008). Large scale mutagenesis in p19(ARF)- and p53-deficient mice identifies cancer genes and their collaborative networks. Cell 133: 727–741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • van Meyel DJ, Thomas JB, Agulnick AD . (2003). Ssdp proteins bind to LIM-interacting co-factors and regulate the activity of LIM-homeodomain protein complexes in vivo. Development 130: 1915–1925.

    Article  CAS  PubMed  Google Scholar 

  • Wu HK, Heng HH, Siderovski DP, Dong WF, Okuno Y, Shi XM et al. (1996). Identification of a human LIM-Hox gene, hLH-2, aberrantly expressed in chronic myelogenous leukaemia and located on 9q33–34.1. Oncogene 12: 1205–1212.

    CAS  PubMed  Google Scholar 

  • Xu Z, Meng X, Cai Y, Liang H, Nagarajan L, Brandt SJ . (2007). Single-stranded DNA-binding proteins regulate the abundance of LIM domain and LIM domain-binding proteins. Genes Dev 21: 942–955.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang XB, Beard BC, Trobridge GD, Wood BL, Sale GE, Sud R et al. (2008). High incidence of leukemia in large animals after stem cell gene therapy with a HOXB4-expressing retroviral vector. J Clin Invest 118: 1502–1510.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Xiaoping Ma and Mayur Patel for expert technical assistance, Samuel Pfaff and Dong Er Zhang for housing the Ssbp2−/− mice in the early stages of these investigations, Gigi Lozano, Richard Behringer, present and former members of the Nagarajan laboratory for helpful discussions, Kim-Anh Vu for assistance with the histology photographs. These studies were supported by HL744409 to LN. The genotyping, flow cytometry facilities and veterinary services were supported by NCI core Grant CA16672.

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Authors and Affiliations

  1. Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Y Wang, H Liang, J Li & L Nagarajan

  2. Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    S Klumpp

  3. Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    H M Amin

  4. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Z Estrov

  5. Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Zweidler-McKay

  6. Departments of Medicine, Cell and Developmental Biology, and Cancer Biology and Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN, USA

    S J Brandt

  7. Novocell Inc., La Jolla, CA, USA

    A Agulnick

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Correspondence to L Nagarajan.

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Wang, Y., Klumpp, S., Amin, H. et al. SSBP2 is an in vivo tumor suppressor and regulator of LDB1 stability. Oncogene 29, 3044–3053 (2010). https://doi.org/10.1038/onc.2010.78

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