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:

Selective activation of NFAT by promyelocytic leukemia protein

Oncogene volume 27, pages 3821–3830 (2008)Cite this article

Abstract

Promyelocytic leukemia (PML) protein is a tumor suppressor with complicated action mechanisms not yet fully understood. In this study, we found that the nuclear factor of activated T cell (NFAT) is an unexpected partner of PML: PML specifically enhanced the transcription activation of NFAT. In PML-null mouse embryonic fibroblasts, no transcription activity of NFAT could be detected. There was a selective requirement of PML isoform in NFAT activation: PML-I and PML-VI, but not PML-IV, increased NFAT transactivation. PML specifically promoted the expression of many, but not all, NFAT-targeted genes. We found a specific binding of PML to NFATc. The interaction of PML with NFATc in vivo was further confirmed by chromatin immunoprecipitation and DNA affinity precipitation assay analysis. The unexpected coupling of PML with NFAT reveals a novel mechanism underlying the diverse physiological functions of PML.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Avots A, Buttmann M, Chuvpilo S, Escher C, Smola U, Bannister AJ et al. (1999). CBP/p300 integrates Raf/Rac-signaling pathways in the transcriptional induction of NF-ATc during T cell activation. Immunity 10: 515–524.

    Article  CAS  Google Scholar 

  • Bischof O, Kirsh O, Pearson M, Itahana K, Pelicci PG, Dejean A . (2002). Deconstructing PML-induced premature senescence. EMBO J 21: 3358–3369.

    Article  CAS  Google Scholar 

  • Bruno S, Ghiotto F, Fais F, Fagioli M, Luzi L, Pelicci PG et al. (2003). The PML gene is not involved in the regulation of MHC class I expression in human cell lines. Blood 101: 3514–3519.

    Article  CAS  Google Scholar 

  • Buschbeck M, Uribesalgo I, Ledl A, Gutierrez A, Minucci S, Muller S et al. (2007). PML4 induces differentiation by Myc destabilization. Oncogene 26: 3415–3422.

    Article  CAS  Google Scholar 

  • Cairo S, De Falco F, Pizzo M, Salomoni P, Pandolfi PP, Meroni G . (2005). PML interacts with Myc, and Myc target gene expression is altered in PML-null fibroblasts. Oncogene 24: 2195–2203.

    Article  CAS  Google Scholar 

  • Condemine W, Takahashi Y, Zhu J, Puvion-Dutilleul F, Guegan S, Janin A et al. (2006). Characterization of endogenous human promyelocytic leukemia isoforms. Cancer Res 66: 6192–6198.

    Article  CAS  Google Scholar 

  • Crabtree GR, Olson EN . (2002). NF-AT signaling: choreographing the social lives of cells. Cell 109: S67–S79.

    Article  CAS  Google Scholar 

  • Crowder C, Dahle O, Davis RE, Gabrielsen OS, Rudikoff S . (2005). PML mediates IFN-α-induced apoptosis in myeloma by regulating TRAIL induction. Blood 105: 1280–1287.

    Article  CAS  Google Scholar 

  • Dellaire G, Bazett-Jones DP . (2004). PML nuclear bodies: dynamic sensors of DNA damage and cellular stress. Bioessays 26: 963–977.

    Article  CAS  Google Scholar 

  • Doucas V, Tini M, Egan DA, Evans RM . (1999). Modulation of CREB binding protein function by the promyelocytic (PML) oncoprotein suggests a role for nuclear bodies in hormone signaling. Proc Natl Acad Sci USA 96: 2627–2632.

    Article  CAS  Google Scholar 

  • Fogal V, Gostissa M, Sandy P, Zacchi P, Sternsdorf T, Jensen K et al. (2000). Regulation of p53 activity in nuclear bodies by a specific PML isoform. EMBO J 19: 6185–6195.

    Article  CAS  Google Scholar 

  • Garcia-Rodriguez C, Rao A . (1998). Nuclear factor of activated T cells (NFAT)-dependent transactivation regulated by the coactivators p300/CREB-binding protein. J Exp Med 187: 2031–2036.

    Article  CAS  Google Scholar 

  • Goddard AD, Yuan JQ, Fairbarin L, Dexter M, Borrow J, Kozak C et al. (1995). Cloning of the murine homolog of the leukemia-associated PML gene. Mamm Genome 6: 732–737.

    Article  CAS  Google Scholar 

  • Guo A, Salomoni P, Luo J, Shih A, Zhong S, Gu W et al. (2000). The function of PML in p53-dependent apoptosis. Nat Cell Biol 2: 730–736.

    Article  CAS  Google Scholar 

  • Ho HY, Lee HH, Lai MZ . (1997). Overexpression of mitogen-activated protein kinase kinase kinase reversed cAMP inhibition of NF-κB in T cells. Eur J Immunol 27: 222–226.

    Article  CAS  Google Scholar 

  • Hogan PG, Chen L, Nardone J, Rao A . (2003). Transcriptional regulation by calcium, calcineurin, and NFAT. Genes Dev 17: 2205–2232.

    Article  CAS  Google Scholar 

  • Ishov AM, Vladimirova OV, Maul GG . (2004). Heterochromatin and ND10 are cell-cycle regulated and phosphorylation-dependent alternate nuclear sites of the transcription repressor Daxx and SWI/SNF protein ATRX. J Cell Sci 117: 3807–3820.

    Article  CAS  Google Scholar 

  • Jensen K, Shiels C, Freemont PS . (2001). PML protein isoforms and the RBCC/TRIM motif. Oncogene 20: 7223–7233.

    Article  CAS  Google Scholar 

  • Latinis KM, Norian LA, Eliason SL, Koretzky GA . (1997). Two NFAT transcription factor binding sites participate in the regulation of CD95 (Fas) ligand expression in activated human T cells. J Biol Chem 272: 31427–31434.

    Article  CAS  Google Scholar 

  • Li H, Leo C, Zhu J, Wu X, O'Neil J, Park EJ et al. (2000). Sequestration and inhibition of Daxx-mediated transcriptional repression by PML. Mol Cell Biol 20: 1784–1796.

    Article  CAS  Google Scholar 

  • Lin DY, Fang HI, Ma AH, Huang YS, Pu YS, Jenster G et al. (2004). Negative modulation of androgen receptor transcriptional activity by Daxx. Mol Cell Biol 24: 10529–10541.

    Article  CAS  Google Scholar 

  • Lin DY, Lai MZ, Ann DK, Shih HM . (2003). Promyelocytic leukemia protein (PML) functions as a glucocorticoid receptor co-activator by sequestering Daxx to the PML oncogenic domains (PODs) to enhance its transactivation potential. J Biol Chem 278: 15958–15965.

    Article  CAS  Google Scholar 

  • Macian F, Garcia-Cozar F, Im SH, Horton HF, Byrne MC, Rao A . (2002). Transcriptional mechanisms underlying lymphocyte tolerance. Cell 109: 719–731.

    Article  CAS  Google Scholar 

  • Metivier R, Penot G, Hubner MR, Reid G, Brand H, Kos M et al. (2003). Estrogen receptor-α directs ordered, cyclical, and combinatorial recruitment of cofactors on a natural target promoter. Cell 115: 751–763.

    Article  CAS  Google Scholar 

  • Möller A, Sirma H, Hofmann TG, Rueffer S, Klimczak E, Dröge W et al. (2003). PML is required for homeodomain-interacting protein kinase 2 (HIPK2)-mediated p53 phosphorylation and cell cycle arrest but is dispensable for the formation of HIPK domains. Cancer Res 63: 4310–4314.

    PubMed  Google Scholar 

  • Perkins ND, Felzien LK, Betts JC, Leung K, Beach DH, Nabel GJ . (1997). Regulation of NF-κB by cyclin-dependent kinases associated with the p300 coactivator. Science 275: 523–527.

    Article  CAS  Google Scholar 

  • Salomoni P, Bernardi R, Bergmann S, Changou A, Tuttle S, Pandolfi PP . (2005). The promyelocytic leukemia protein PML regulates c-Jun function in response to DNA damage. Blood 105: 3686–3690.

    Article  CAS  Google Scholar 

  • Salomoni P, Pandolfi PP . (2002). The role of PML in tumor suppression. Cell 108: 165–170.

    Article  CAS  Google Scholar 

  • Tsai EY, Yie J, Thanos D, Goldfeld AE . (1996). Cell-type-specific regulation of the human tumor necrosis factor alpha gene in B cells and T cells by NFATp and ATF-2/JUN. Mol Cell Biol 16: 5232–5244.

    Article  CAS  Google Scholar 

  • von Mikecz A, Zhang S, Montminy M, Tan EM, Hemmerich P . (2000). CREB-binding protein (CBP)/p300 and RNA polymerase II colocalize in transcriptionally active domains in the nucleus. J Cell Biol 150: 265–273.

    Article  CAS  Google Scholar 

  • Wang J, Shiels C, Sasieni P, Wu PJ, Islam SA, Freemont PS et al. (2004). Promyelocytic leukemia nuclear bodies associate with transcriptionally active genomic regions. J Cell Biol 164: 515–526.

    Article  CAS  Google Scholar 

  • Wang Q, Ji Y, Wang X, Evers BM . (2000). Isolation and molecular characterization of the 5′-upstream region of the human TRAIL gene. Biochem Biophys Res Commun 276: 466–471.

    Article  CAS  Google Scholar 

  • Wang ZG, Ruggero D, Ronchetti S, Zhong S, Gaboli M, Rivi R et al. (1998). PML is essential for multiple apoptotic pathways. Nat Genet 20: 266–272.

    Article  CAS  Google Scholar 

  • Wu CC, Hsu SC, Shih HM, Lai MZ . (2003a). NFATc is a target of p38 mitogen activated protein kinase in T cells. Mol Cell Biol 23: 6442–6454.

    Article  CAS  Google Scholar 

  • Wu WS, Vallian S, Seto E, Yang WM, Edmondson D, Roth S et al. (2001). The growth suppressor PML represses transcription by functionally and physically interacting with histone deacetylases. Mol Cell Biol 21: 2259–2268.

    Article  CAS  Google Scholar 

  • Wu WS, Xu ZX, Hittelman WN, Salomoni P, Pandolfi PP, Chang KS . (2003b). Promyelocytic leukemia protein sensitizes tumor necrosis factor alpha-induced apoptosis by inhibiting the NF-κB survival pathway. J Biol Chem 278: 12294–12304.

    Article  CAS  Google Scholar 

  • Wu WS, Xu ZX, Ran R, Meng F, Chang KS . (2002). Promyelocytic leukemia protein PML inhibits Nur77-mediated transcription through specific functional interactions. Oncogene 21: 3925–3933.

    Article  CAS  Google Scholar 

  • Youn HD, Chatila TA, Liu JO . (2000). Integration of calcineurin and MEF2 signals by the coactivator p300 during T-cell apoptosis. EMBO J 19: 4323–4331.

    Article  CAS  Google Scholar 

  • Zhong S, Salomoni P, Pandolfi PP . (2000). The transcriptional role of PML and the nuclear body. Nat Cell Biol 2: E85–E90.

    Article  CAS  Google Scholar 

  • Zhu Y, Saunders MA, Yeh H, Deng WG, Wu KK . (2002). Dynamic regulation of cyclooxygenase-2 promoter activity by isoforms of CCAAT/enhancer-binding proteins. J Biol Chem 27: 6923–6928.

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by Grants NSC93-2320-B001-029 and NSC 94-2320-B001-012 from the National Science Council, and Grant AS-95-TP-B02-2 from Academia Sinica, Taiwan, R.O.C. We thank Dr Gerd G. Maul for PML-null MEFs, Drs Gerald Crabtree, Ron Evans, Laurie H Glimcher, Hsiou-Chi Liou and Anjana Rao for plasmids, and Dr Harry Wilson for editing the manuscript.

Author information

Authors and Affiliations

  1. Graduate Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, ROC

    Y-H Lo & M-Z Lai

  2. Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan, ROC

    Y-H Lo, C-C Wu & M-Z Lai

  3. Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, ROC

    H-M Shih

  4. Graduate Institute of Immunology, National Taiwan University School of Medicine, Taipei, Taiwan, ROC

    M-Z Lai

Authors
  1. Y-H Lo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. C-C Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. H-M Shih
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M-Z Lai
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M-Z Lai.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lo, YH., Wu, CC., Shih, HM. et al. Selective activation of NFAT by promyelocytic leukemia protein. Oncogene 27, 3821–3830 (2008). https://doi.org/10.1038/onc.2008.2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2008.2

Keywords

This article is cited by

Search

Advanced search

Quick links