Skip to main content
SpringerLink
Log in

Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

The proto-oncogene, pleomorphic adenoma gene-like 2 (PLAGL2), is implicated in a variety of cancers including acute myeloid leukemia (AML), malignant glioma, colon cancer, and lung adenocarcinoma. There is additional evidence that PLAGL2 can function as a tumor suppressor by initiating cell cycle arrest and apoptosis. Interestingly, PLAGL2 has also been implicated in human myelodysplastic syndrome, a disease that is characterized by ineffective hematopoiesis and can lead to fatal cytopenias (low blood counts) as a result of increased apoptosis in the marrow, or, in about one-third of cases, can progress to AML. To gain a better understanding of the actions of PLAGL2 in human myeloid cells, we generated a stable PLAGL2-inducible cell line, using human promonocytic U937 cells. PLAGL2 expression inhibited cell proliferation which correlated with an accumulation of cells in G1, apoptotic DNA-laddering, an increase in caspase 3, 8, and 9 activity, and a loss of mitochondrial transmembrane potential. There was significant increase in the p53 homologue, p73, with PLAGL2 expression, and consistent with mechanisms of p73-regulated cell cycle control and apoptosis, there was increased expression of known p73 target genes p21, DR5, TRAIL, and Bax. PLAGL2-induced cell cycle block was abolished in the presence of p73 siRNA. Together, these data support a role for PLAGL2 in cell cycle regulation and apoptosis via activation of p73.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Abdollahi A (2007) LOT1 (ZAC1/PLAGL1) and its family members: mechanisms and functions. J Cell Physiol 210:16–25

    Article  PubMed  CAS  Google Scholar 

  2. Kas K, Voz ML, Hensen K, Meyen E, Van de Ven WJM (1998) Transcriptional activation capacity of the novel PLAG family of zinc finger proteins. J Biol Chem 273:23026–23032

    Article  PubMed  CAS  Google Scholar 

  3. Hensen K, Van Valckenborgh IC, Kas K, Van de Ven WJ, Voz ML (2002) The tumorigenic diversity of the three PLAG family members is associated with different DNA binding capacities. Cancer Res 62:1510–1517

    PubMed  CAS  Google Scholar 

  4. Kas K, Voz ML, Roijer E, Astrom AK, Meyen E, Stenman G et al (1997) Promoter swapping between the genes for a novel zinc finger protein and beta-catenin in pleiomorphic adenomas with t(3;8)(p21;q12) translocations. Nat Genet 15:170–174

    Article  PubMed  CAS  Google Scholar 

  5. Astrom A, D’Amore ES, Sainati L, Panarello C, Morerio C, Mark J et al (2000) Evidence of involvement of the PLAG1 gene in lipoblastomas. Int J Oncol 16:1107–1110

    PubMed  CAS  Google Scholar 

  6. Hibbard MK, Kozakewich HP, Dal CP, Sciot R, Tan X, Xiao S et al (2000) PLAG1 fusion oncogenes in lipoblastoma. Cancer Res 60:4869–4872

    PubMed  CAS  Google Scholar 

  7. Zatkova A, Rouillard JM, Hartmann W, Lamb BJ, Kuick R, Eckart M et al (2004) Amplification and overexpression of the IGF2 regulator PLAG1 in hepatoblastoma. Genes Chromosomes Cancer 39:126–137

    Article  PubMed  CAS  Google Scholar 

  8. Spengler D, Villalba M, Hoffmann A, Pantaloni C, Houssami S, Bockaert J et al (1997) Regulation of apoptosis and cell cycle arrest by Zac1, a novel zinc finger protein expressed in the pituitary gland and the brain. EMBO J 16:2814–2825

    Article  PubMed  CAS  Google Scholar 

  9. Furukawa T, Adachi Y, Fujisawa J, Kambe T, Yamaguchi-Iwai Y, Sasaki R et al (2001) Involvement of PLAGL2 in activation of iron deficient- and hypoxia-induced gene expression in mouse cell lines. Oncogene 20:4718–4727

    Article  PubMed  CAS  Google Scholar 

  10. Mizutani A, Furukawa T, Adachi Y, Ikehara S, Taketani S (2002) A zinc-finger protein, PLAGL2, induces the expression of a proapoptotic protein Nip3, leading to cellular apoptosis. J Biol Chem 277:15851–15858

    Article  PubMed  CAS  Google Scholar 

  11. Yang YS, Yang MC, Guo Y, Williams OW, Weissler JC (2009) PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity. Am J Physiol Lung Cell Mol Physiol 297:L455–L466

    Article  PubMed  CAS  Google Scholar 

  12. Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV et al (2010) PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell 17:497–509

    Article  PubMed  CAS  Google Scholar 

  13. Yang YS, Yang MC, Weissler JC (2011) Pleiomorphic adenoma gene-like 2 expression is associated with the development of lung adenocarcinoma and emphysema. Lung Cancer. doi:10.1016/j.lungcan.2011.02.006

  14. Landrette SF, Kuo YH, Hensen K, Barjesteh van Waalwijk van Doorn-Khosrovani S, Perrat PN, Van de Ven WJ et al (2005) Plag1 and Plagl2 are oncogenes that induce acute myeloid leukemia in cooperation with Cbfb-MYH11. Blood 105:2900–2907

    Article  PubMed  CAS  Google Scholar 

  15. Landrette SF, Madera D, He F, Castilla LH (2011) The transcription factor PlagL2 activates Mpl transcription and signaling in hematopoietic progenitor and leukemia cells. Leukemia 25:655–662

    Article  PubMed  CAS  Google Scholar 

  16. Mackinnon RN, Selan C, Wall M, Baker E, Nandurkar H, Campbell LJ (2010) The paradox of 20q11.21 amplification in a subset of cases of myeloid malignancy with chromosome 20 deletion. Genes Chromosomes Cancer 49:998–1013

    Article  PubMed  CAS  Google Scholar 

  17. Mhawech P, Saleem A (2001) Myelodysplastic syndrome: review of the cytogenetic and molecular data. Crit Rev Oncol Hematol 40:229–238

    Article  PubMed  CAS  Google Scholar 

  18. Wezensky SJ, Hanks TS, Wilkison MJ, Ammons MC, Siemsen DW, Gauss KA (2010) Modulation of PLAGL2 transactivation by positive cofactor 2 (PC2), a component of the ARC/Mediator complex. Gene 452:22–34

    Article  PubMed  CAS  Google Scholar 

  19. Sundstrom C, Nilsson K (1976) Establishment and characterization of a human histiocytic lymphoma cell line (U-937). Int J Cancer 17:565–577

    Article  PubMed  CAS  Google Scholar 

  20. Harris P, Ralph P (1985) Human leukemic models of myelomonocytic development: a review of the HL-60 and U937 cell lines. J Leukoc Biol 37:407–422

    PubMed  CAS  Google Scholar 

  21. Boer J, Bonten-Surtel J, Grosveld G (1998) Overexpression of the nucleoporin CAN/NUP214 induces growth arrest, nucleocytoplasmic transport defects, and apoptosis. Mol Cell Biol 18:1236–1247

    PubMed  CAS  Google Scholar 

  22. Ammons MC, Siemsen DW, Nelson-Overton LK, Quinn MT, Gauss KA (2007) Binding of pleomorphic adenoma gene-like 2 to the tumor necrosis factor (TNF)-alpha-responsive region of the NCF2 promoter regulates p67(phox) expression and NADPH oxidase activity. J Biol Chem 282:17941–17952

    Article  PubMed  CAS  Google Scholar 

  23. Simon HU, Haj-Yehia A, Levi-Schaffer F (2000) Role of reactive oxygen species (ROS) in apoptosis induction. Apoptosis 5:415–418

    Article  PubMed  CAS  Google Scholar 

  24. Ramadan S, Terrinoni A, Catani MV, Sayan AE, Knight RA, Mueller M et al (2005) p73 induces apoptosis by different mechanisms. Biochem Biophys Res Commun 331:713–717

    Article  PubMed  CAS  Google Scholar 

  25. Holcakova J, Ceskova P, Hrstka R, Muller P, Dubska L, Coates PJ et al (2008) The cell type-specific effect of TAp73 isoforms on the cell cycle and apoptosis. Cell Mol Biol Lett 13:404–420

    Article  PubMed  CAS  Google Scholar 

  26. Blint E, Phillips AC, Kozlov S, Stewart CL, Vousden KH (2002) Induction of p57(KIP2) expression by p73beta. Proc Natl Acad Sci USA 99:3529–3534

    Article  PubMed  Google Scholar 

  27. Zawacka-Pankau J, Kostecka A, Sznarkowska A, Hedstrom E, Kawiak A (2010) p73 tumor suppressor protein: a close relative of p53 not only in structure but also in anti-cancer approach? Cell Cycle 9:720–728

    Article  PubMed  CAS  Google Scholar 

  28. Besson A, Dowdy SF, Roberts JM (2008) CDK inhibitors: cell cycle regulators and beyond. Dev Cell 14:159–169

    Article  PubMed  CAS  Google Scholar 

  29. Schmelz K, Wagner M, Dorken B, Tamm I (2005) 5-Aza-2′-deoxycytidine induces p21WAF expression by demethylation of p73 leading to p53-independent apoptosis in myeloid leukemia. Int J Cancer 114:683–695

    Article  PubMed  CAS  Google Scholar 

  30. Stiewe T, Putzer BM (2001) p73 in apoptosis. Apoptosis 6:447–452

    Article  PubMed  CAS  Google Scholar 

  31. Zaika A, Irwin M, Sansome C, Moll UM (2001) Oncogenes induce and activate endogenous p73 protein. J Biol Chem 276:11310–11316

    Article  PubMed  CAS  Google Scholar 

  32. Stiewe T, Putzer BM (2000) Role of the p53-homologue p73 in E2F1-induced apoptosis. Nat Genet 26:464–469

    Article  PubMed  CAS  Google Scholar 

  33. Irwin M, Marin MC, Phillips AC, Seelan RS, Smith DI, Liu W et al (2000) Role for the p53 homologue p73 in E2F–1-induced apoptosis. Nature 407:645–648

    Article  PubMed  CAS  Google Scholar 

  34. Gong JG, Costanzo A, Yang HQ, Melino G, Kaelin WG Jr, Levrero M et al (1999) The tyrosine kinase c-Abl regulates p73 in apoptotic response to cisplatin-induced DNA damage. Nature 399:806–809

    Article  PubMed  CAS  Google Scholar 

  35. Agami R, Bernards R (2000) Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 102:55–66

    Article  PubMed  CAS  Google Scholar 

  36. Yuan ZM, Shioya H, Ishiko T, Sun X, Gu J, Huang YY et al (1999) p73 is regulated by tyrosine kinase c-Abl in the apoptotic response to DNA damage. Nature 399:814–817

    Article  PubMed  CAS  Google Scholar 

  37. Halazonetis TD, Gorgoulis VG, Bartek J (2008) An oncogene-induced DNA damage model for cancer development. Science 319:1352–1355

    Article  PubMed  CAS  Google Scholar 

  38. Yang A, Kaghad M, Wang Y, Gillett E, Fleming MD, Dotsch V et al (1998) p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol Cell 2:305–316

    Article  PubMed  CAS  Google Scholar 

  39. Irwin MS, Kaelin WG (2001) p53 family update: p73 and p63 develop their own identities. Cell Growth Differ 12:337–349

    PubMed  CAS  Google Scholar 

  40. Benard J, Douc-Rasy S, Ahomadegbe JC (2003) TP53 family members and human cancers. Hum Mutat 21:182–191

    Article  PubMed  CAS  Google Scholar 

  41. Moll UM, Slade N (2004) p63 and p73: roles in development and tumor formation. Mol Cancer Res 2:371–386

    PubMed  CAS  Google Scholar 

  42. Vikhanskaya F, Toh WH, Dulloo I, Wu Q, Boominathan L, Ng HH et al (2007) p73 supports cellular growth through c-Jun-dependent AP-1 transactivation. Nat Cell Biol 9:698–705

    Article  PubMed  CAS  Google Scholar 

  43. Collavin L, Lunardi A, Del SG (2010) p53-family proteins and their regulators: hubs and spokes in tumor suppression. Cell Death Differ 17:901–911

    Article  PubMed  CAS  Google Scholar 

  44. Campioni D, Secchiero P, Corallini F, Melloni E, Capitani S, Lanza F et al (2005) Evidence for a role of TNF-related apoptosis-inducing ligand (TRAIL) in the anemia of myelodysplastic syndromes. Am J Pathol 166:557–563

    Article  PubMed  CAS  Google Scholar 

  45. Liu PY, Chan JY, Lin HC, Wang SL, Liu ST, Ho CL et al (2008) Modulation of the cyclin-dependent kinase inhibitor p21(WAF1/Cip1) gene by Zac1 through the antagonistic regulators p53 and histone deacetylase 1 in HeLa Cells. Mol Cancer Res 6:1204–1214

    Article  PubMed  CAS  Google Scholar 

  46. Blundell R, Harrison DJ, O’Dea S (2004) p21(Waf1/Cip1) regulates proliferation and apoptosis in airway epithelial cells and alternative forms have altered binding activities. Exp Lung Res 30:447–464

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Dr. Nicole Meissner and Dr. George Gauss for their critical reading of the manuscript. This work was supported by the National Institutes of Health Grant P20 RR-024237.

Conflict of interest

The authors declare they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Immunology and Infectious Diseases, Montana State University, 960 Technology Blvd., Bozeman, MT, 59718, USA

    Tracey S. Hanks & Katherine A. Gauss

Authors
  1. Tracey S. Hanks
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Katherine A. Gauss
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Katherine A. Gauss.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hanks, T.S., Gauss, K.A. Pleomorphic adenoma gene-like 2 regulates expression of the p53 family member, p73, and induces cell cycle block and apoptosis in human promonocytic U937 cells. Apoptosis 17, 236–247 (2012). https://doi.org/10.1007/s10495-011-0672-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-011-0672-3

Keywords

Search

Navigation