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:

Transcriptional Control and Signal Transduction

ICER expression inhibits leukemia phenotype and controls tumor progression

Abstract

The inducible cyclic AMP (cAMP) early repressor (ICER) and cAMP response element-binding protein (CREB) are transcriptional regulators of the cAMP-mediated signaling pathway. CREB has been demonstrated to be upregulated in the majority of childhood leukemias contributing to disease progression, whereas ICER, its endogenous repressor, was found to be downregulated. Our research focus has been the function of restored ICER expression. ICER exogenously expressed in cell lines decreases CREB protein level and induces a lowered clonogenic potential in vitro. It decreases the ability of HL60 to invade the extramedullary sites and to promote bone marrow angiogenesis in nonobese diabetic–severe combined immunodeficient mice, demonstrating its potential effects on tumor progression. ICER represses the majority of 96 target genes upregulated by CREB. It binds CRE promoters and controls gene expression restoring the normal regulation of major cellular pathways. ICER is subjected to degradation through a constitutively active form of the extracellular signal-regulated protein kinase, which drives it to the proteasome. We propose that ICER is downregulated in HL60 to preserve CREB overexpression, which disrupts normal myelopoiesis and promotes blast proliferation. These findings define the function of ICER as a tumor suppressor in leukemia. Unbalanced CREB/ICER expression needs to be considered a pathogenetic feature in leukemogenesis. The molecular characterization of this pathway could be useful for novel therapeutic strategies.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Molina CA, Foulkes NS, Lalli E, Sassone-Corsi P . Inducibility and negative autoregulation of CREM: an alternative promoter directs the expression of ICER, an early response repressor. Cell 1993; 75: 875–886.

    Article  CAS  PubMed  Google Scholar 

  2. Razavi R, Ramos JC, Yehia G, Schlotter F, Molina CA . ICER-IIg is a tumor suppressor that mediates the antiproliferative activity of cAMP. Oncogene 1998; 17: 3015–3019.

    Article  CAS  PubMed  Google Scholar 

  3. Folco EJ, Koren G . Degradation of the inducible cAMP early repressor (ICER) by the ubiquitin-proteasome pathway. Biochem J 1997; 328: 37–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Haus-Seuffert P, Meisterernst M . Mechanism of transcriptional activation of cAMP-responsive element binding protein CREB. Mol Cell Biochem 2005; 212: 5–9.

    Article  Google Scholar 

  5. Mayr B, Montminy M . Transcriptional regulation by the phosphorylation-dependent factor CREB. Nat Rev Mol Cell Biol 2001; 2: 599–609.

    Article  CAS  PubMed  Google Scholar 

  6. Shankar DB, Cheng JC, Kinjo K, Federman N, Moore TB, Gill A et al. The role of CREB as proto-oncogene in hematopoiesis and in acute myeloid leukemia. Cancer Cell 2005; 7: 351–362.

    Article  CAS  PubMed  Google Scholar 

  7. Jaworski J, Mioduszewska B, Sanchez-Capelo A, Figiel I, Habas A, Gozdz A et al. Inducible cAMP early repressor, an endogenous antagonist of cAMP responsive element-binding protein, evokes neuronal apoptosis in vitro. J Neurosci 2003; 23: 4519–4526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Yan C, Ding B, Shishido T, Itoh S, Jeon KI, Liu W et al. Activation of extracellular signal-regulated kinase 5 reduces cardiac apoptosis and dysfunction via inhibition of a phosphodiesterase 3A/inducible cAMP early repressor feedback loop. Circ Res 2007; 100: 510–519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Servillo G, Viola Magni M, Sassone-Corsi P . Coupling cAMP signaling to transcription in the liver: pivotal role of CREB and CREM. Exp Cell Res 2002; 275: 143–154.

    Article  CAS  PubMed  Google Scholar 

  10. Memin E, Yehia G, Razavi R, Molina CA . ICER reverses tumorigenesis of rat prostate tumor cells without affecting cell growth. Prostate 2002; 53: 225–231.

    Article  CAS  PubMed  Google Scholar 

  11. Peri A, Conforti B, Baglioni-Peri S, Luciani P, Cioppi F, Buci L et al. Expression of cyclic adenosine 3′,5′-monophosphate (cAMP)-responsive element binding protein and inducible-cAMP early repressor genes in growth hormone-secreting pituitary adenomas with or without mutations of the Gs alpha gene. J Clin Endocrinol Metab 2001; 86: 2111–2117.

    CAS  PubMed  Google Scholar 

  12. Pigazzi M, Ricotti E, Germano G, Faggian D, Aricò M, Basso G . cAMP response element binding protein (CREB) overexpression in childhood acute lymphoblastic and myeloid leukemia. Haematologica 2007; 92: 1435–1437.

    Article  CAS  PubMed  Google Scholar 

  13. Cheng JC, Esparza S, Sandoval S, Shankar D, Fu C, Sakamoto KM . Potential role od CREB as a prognostic marker in acute myeloid leukemia. Future Oncol 2007; 3: 475–480.

    Article  CAS  PubMed  Google Scholar 

  14. Schwaninger M, Blume R, Oetjen E, Lux G, Knepel WS . Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization. J Biol Chem 1993; 268: 5168–5177.

    CAS  PubMed  Google Scholar 

  15. Pillozzi S, Brizzi MF, Bernabei PA, Bartolozzi B, Caporale R, Basile V et al. Vegfr-1 (flt-1), β1 integrin and herg k+ channel form a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 2007; 110: 1230–1250.

    Article  Google Scholar 

  16. Steg A, Wang W, Blanquicett C, Grunda JM, Eltoum IA, Wang K et al. Multiple gene expression analyses in paraffin-ambedded tissues by taqman low-density array: application to hedgehog and Wnt pathway analysis in ovarian endometrioid adenocarcinoma. J Mol Diagn 2006; 8: 76–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Langmann T, Mauerer R, Schmitz G . Human ATP-Binding cassette transporter TaqMan low density array: analysis of macrophage differentiation and foam cell formation. Clin Chem 2006; 52: 310–313.

    Article  CAS  PubMed  Google Scholar 

  18. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods 2001; 25: 402–408.

    Article  CAS  PubMed  Google Scholar 

  19. Cheng JC, Kinio K, Judelson DR, Chang J, Wu WS, Schmid U et al. CREB is a critical regulator of normal hematopoiesis and leukemogenesis. Blood 2008; 111: 1182–1192.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang X, Odom DT, Koo SH, Conkright MD, Canettieri G, Best J et al. Genome-wide analysis of cAMP-response element binding protein occupancy, phosphorylation, and target gene activation in human tissues. Proc Natl Acad Sci USA 2005; 102: 4459–4464.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Arakawa K, Kono N, Yamada Y, Mori H, Tomita M . KEGG-based pathway visualization tool for complex omics data. In Silico Biol 2005; 5: 419–423.

    CAS  PubMed  Google Scholar 

  22. Cammenga J, Niebuhr B, Horn S, Bergholz U, Putz G, Buchholz F et al. RUNX1 DNA-binding mutants, associated with minimally differentiated acute myelogenous leukemia, disrupt myeloid differentiation. Cancer Res 2007; 67: 537–545.

    Article  CAS  PubMed  Google Scholar 

  23. Harhaj NS, Sun SC, Harhaj EW . Activation of NF-kappa B by the human T cell leukemia virus type I Tax oncoprotein is associated with ubiquitin-dependent relocalization of I kappa B kinase. J Biol Chem 2007; 282: 4185–4192.

    Article  CAS  PubMed  Google Scholar 

  24. Milella M, Konopleva M, Precupanu CM, Tabe Y, Ricciardi MR, Gregorj C et al. MEK blockade converts AML differentiating response to retinoids into extensive apoptosis. Blood 2007; 109: 2121–2129.

    Article  CAS  PubMed  Google Scholar 

  25. Berman JN, Look AT . Targeting transcription factors in acute leukemia in children. Curr Drug Targets 2007; 8: 727–737.

    Article  CAS  PubMed  Google Scholar 

  26. Koldehoff M, Steckel NK, Beelen DW, Elmaagacli AH . Therapeutic application of small interfering RNA directed against bcr-abl transcripts to a patient with imatinib-resistant chronic myeloid leukaemia. Clin Exp Med 2007; 7: 47–55.

    Article  CAS  PubMed  Google Scholar 

  27. Dasmahapatra G, Yerram N, Dai Y, Dent P, Grant S . Synergistic interactions between vorinostat and sorafenib in chronic myelogenous leukemia cells involve Mcl-1 and p21CIP1 down-regulation. Clin Cancer Res 2007; 13: 4280–4290.

    Article  CAS  PubMed  Google Scholar 

  28. Manna PR, Dyson MT, Eubank DW, Clark BJ, Lalli E, Sassone-Corsi P et al. Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Mol Endocrinol 2002; 16: 184–199.

    Article  CAS  PubMed  Google Scholar 

  29. Peri A, Luciani P, Tonacchera M, Agretti P, Baglioni-Peri S, Buci L et al. Expression of cAMP-responsive element binding protein and inducible cAMP early repressor in hyperfunctioning thyroid adenomas. J Clin Endocrinol Metab 2002; 146: 759–766.

    CAS  Google Scholar 

  30. Steigedal TS, Bruland T, Misund K, Thommesen L, Laegreid A . Inducible cAMP early repressor suppresses gastrin-mediated activation of cyclin D1 and c-Fos gene expression. Am J Physiol Gastrointest Liver Physiol 2007; 292: 1062–1069.

    Article  Google Scholar 

  31. Jeon SH, Chae BC, Kim HA, Seo GY, Seo DW, Chun GT et al. The PKA/CREB pathway is closely involved in VEGF expression in mouse macrophages. Mol Cells 2007; 23: 23–29.

    CAS  PubMed  Google Scholar 

  32. Krejsgaard T, Vetter-Kauczok CS, Woetmann A, Lovato P, Labuda T, Eriksen KW et al. Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma. Leukemia 2006; 20: 1759–1766.

    Article  CAS  PubMed  Google Scholar 

  33. Wang M, Zhang W, Crisostomo P, Markel T, Meldrum KK, Fu XY et al. STAT3 mediates bone marrow mesenchymal stem cell VEGF production. J Mol Cell Cardiol 2007; 42: 1009–1015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lin YG, Kunnumakkara AB, Nair A, Merritt WM, Han LY, Armaiz-Pena GN et al. Curcumin inhibits tumor growth and angiogenesis in ovarian carcinoma by targeting the nuclear factor-kappaB pathway. Clin Cancer Res 2007; 13: 3423–3430.

    Article  CAS  PubMed  Google Scholar 

  35. Chang JH, Vuppalanchi D, van Niekerk E, Trepel JB, Schanen NC, Twiss JL . PC12 cells regulate inducible cyclic AMP (cAMP) element repressor expression to differentially control cAMP response element-dependent transcription in response to nerve growth factor and cAMP. J Neurochem 2006; 99: 1517–1530.

    Article  CAS  PubMed  Google Scholar 

  36. Misund K, Steigedal TS, Laegreid A, Thommesen L . Inducible cAMP early repressor splice variants ICER I and IIgamma both repress transcription of c-fos and chromogranin A. J Cell Biochem 2007; 101: 1532–1544.

    Article  CAS  PubMed  Google Scholar 

  37. Abderrahmani A, Cheviet S, Ferdaoussi M, Coppola T, Waeber G, Regazzi R . ICER induced by hyperglycemia represses the expression of genes essential for insulin exocytosis. EMBO J 2006; 25: 977–986.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu Y, Fang F, St Clair DK, Josson S, Sompol P, Spasojevic I et al. Suppression of RelB-mediated manganese superoxide dismutase expression reveals a primary mechanism for radiosensitization effect of 1 {alpha},25-dihydroxyvitamin D3 in prostate cancer cells. Mol Cancer Ther 2007; 6: 2048–2056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang X, Belguise K, Kersual N, Kirsch KH, Mineva ND, Galtier F et al. Oestrogen signalling inhibits invasive phenotype by repressing RelB and its target BCL2. Nat Cell Biol 2007; 9: 470–478.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Plaza-Menacho I, van der Sluis T, Hollema H, Gimm O, Buys CH, Magee AI et al. Ras/ERK1/2-mediated STAT3 Ser727 phosphorylation by familial medullary thyroid carcinoma-associated RET mutants induces full activation of STAT3 and is required for c-fos promoter activation, cell mitogenicity, and transformation. J Biol Chem 2007; 282: 6415–6424.

    Article  CAS  PubMed  Google Scholar 

  41. Nandi A, Rapoport A . Expression of PDZ-binding kinase (PBK) is regulated by cell cycle-specific transcription factors E2F and CREB/ATF. Leukemia Research 2007; 30: 437–447.

    Article  Google Scholar 

  42. Esparza S, Chang J, Shankar DB, Zhang B, Nelson SF, Sakamoto KM . CREB regulates Meis1 expression in normal and malignant hematopoietic cells. Leukemia 2008; 22: 665–667.

    Article  CAS  PubMed  Google Scholar 

  43. Tucker SJ, Rae C, Littlejohn AF, Paul A, MacEvan DJ . Switching leukaemia cell phenotype between life and death. PNAS 2004; 101: 12940–12945.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Zhou H, Gao J, Lu ZY, Lu L, Dai W, Xu M . Role of c-Fos/JunD in protecting stress-induced cell death. Cell Prolif 2007; 40: 431–444.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Zhang W, Liu HT . MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res 2002; 12: 9–18.

    Article  CAS  PubMed  Google Scholar 

  46. Morales V, Gonzalez-Robayna I, Santana MP, Hernandez I, Fanjul LF . Tumor necrosis factor-alpha activates transcription of inducible repressor form of 3′,5′-cyclic adenosine 5′-monophosphate-responsive element binding modulator and represses P450 aromatase and inhibin alpha-subunit expression in rat ovarian granulosa cells by a p44/42 mitogen-activated protein kinase-dependent mechanism. Endocrinology 2006; 147: 5932–5939.

    Article  CAS  PubMed  Google Scholar 

  47. Yan C, Clint LM, Jun-ichi A . Regulation of phosphodiesterase 3 and inducible cAMP early repressor in the hearth. Circ Res 2007; 100: 489–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Hu Y, Lund IV, Gravielle MC, Farb DH, Brooks-Kayal AR, Russek SJ . Surface expression of GABA(A) receptors is transcriptionally conmtrolled by the interplay of CREB and its binding partner ICER. J Biol Chem 2008; 283: 9328–9340.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Mouravlev A, Young D, During MJ . Phosphorylation-dependent degradation of transgenic CREB protein initiated by heterodimerization. Brain Res 2007; 1130: 31–37.

    Article  CAS  PubMed  Google Scholar 

  50. Siu YT, Jin DY . CREB- a real culprit in oncogenesis. FEBS J 2007; 274: 3224–3232.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by University of Padua, ‘Fondazione Città della Speranza’, by Murst PRIN, AIRC, Murst CNR. The sponsors of this study are public or nonprofit organizations that support science, in general. They had no function in gathering, analyzing or interpreting the data. We thank Leonardo Salviati, Eva Trevisson, Maria Cristina Baldoin, Giuseppe Germano, Emanuela Ricotti, Prof.ssa Annarosa Arcangeli and Serena Pillozzi for their collaboration. We thank Ruth Black and Colette Case for manuscript editing.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to M Pigazzi.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pigazzi, M., Manara, E., Baron, E. et al. ICER expression inhibits leukemia phenotype and controls tumor progression. Leukemia 22, 2217–2225 (2008). https://doi.org/10.1038/leu.2008.244

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.244

Keywords

This article is cited by

Search

Quick links