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Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness

Oncogene volume 29, pages 2916–2926 (2010)Cite this article

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A Corrigendum to this article was published on 06 November 2012

Abstract

The highly conserved NOTCH signaling pathway has many essential functions in the development of diverse cells, tissues and organs from Drosophila to humans, and dysregulated NOTCH signaling contributes to several disorders, including vascular and bone defects, as well as several cancers. Here we describe a novel mechanism of NOTCH regulation by reciprocal inhibition of two NOTCH downstream effectors: Deltex1 and HES1. This mechanism appears to regulate invasion of osteosarcoma cells, as Deltex1 blocks osteosarcoma invasiveness by downregulating NOTCH/HES1 signaling. The inhibitory effect of endogenous Deltex1 on NOTCH signaling is mediated through binding with the intracellular domain of NOTCH and ubiquitination and degradation of NOTCH receptors. Conversely, we show that the NOTCH target gene HES1 causes transcriptional inhibition of Deltex1 by directly binding to the promoter of Deltex1. An HES1 binding site is identified 400 bp upstream of the transcription start site of Deltex1. HES1-mediated repression of Deltex1 requires the C-terminal H3/H4 and WRPW domains of HES1, which associate with the TLE/Groucho corepressors. Taken together, we define a molecular mechanism regulating NOTCH signaling by reciprocal inhibition of the NOTCH target genes HES1 and Deltex1 in mammalian cells. This mechanism may have important clinical implications for targeting NOTCH signaling in osteosarcoma and other cancers.

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References

  • Allenspach E, Maillard I, Aster J, Pear W . (2002). Notch signaling in cancer. Cancer Biol Ther 1: 466–476.

    Article  Google Scholar 

  • Artavanis-Tsakonas S, Rand MD, Lake RJ . (1999). Notch signaling: cell fate control and signal integration in development. Science 284: 770–776.

    Article  CAS  Google Scholar 

  • Axelson H . (2004). The Notch signaling cascade in neuroblastoma: role of the basic helix-loop-helix proteins HASH-1 and HES-1. Cancer Lett 204: 171–178.

    Article  CAS  Google Scholar 

  • Castella P, Sawai S, Nakao K, Wagner JA, Caudy M . (2000). HES-1 repression of differentiation and proliferation in PC12 cells: role for the helix 3-helix 4 domain in transcription repression. Mol Cell Biol 20: 6170–6183.

    Article  CAS  Google Scholar 

  • Chen Y, Fischer WH, Gill GN . (1997). Regulation of the ERBB-2 promoter by RBPJkappa and NOTCH. J Biol Chem 272: 14110–14114.

    Article  CAS  Google Scholar 

  • Cinnamon E, Paroush Z . (2008). Context-dependent regulation of Groucho/TLE-mediated repression. Curr Opin Genet Dev 18: 435–440.

    Article  CAS  Google Scholar 

  • Fortini M . (2002). Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling. Nat Rev Mol Cell Biol 3: 673–684.

    Article  CAS  Google Scholar 

  • Hori K, Fostier M, Ito M, Fuwa TJ, Go MJ, Okano H et al. (2004). Drosophila deltex mediates suppressor of hairless-independent and late-endosomal activation of Notch signaling. Development 131: 5527–5537.

    Article  CAS  Google Scholar 

  • Hughes DPM, Thomas DG, Giordano TJ, Baker LH, McDonagh KT . (2004). Cell surface expression of epidermal growth factor receptor and Her-2 with nuclear expression of Her-4 in primary osteosarcoma. Cancer Res 64: 2047–2053.

    Article  CAS  Google Scholar 

  • Iso T, Kedes L, Hamamori Y . (2003). HES and HERP families: multiple effectors of the notch signaling pathway. J Cell Physiol 194: 237–255.

    Article  CAS  Google Scholar 

  • Itoh M, Kim C, Palardy G, Oda T, Jiang Y, Maust D et al. (2003). Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta. Dev Cell 4: 67–82.

    Article  CAS  Google Scholar 

  • Izon DJ, Aster JC, He Y, Weng A, Karnell FG, Patriub V et al. (2002). Deltex1 redirects lymphoid progenitors to the B cell lineage by antagonizing Notch1. Immunity 16: 231–243.

    Article  CAS  Google Scholar 

  • Jackson P, Eldridge A, Freed E, Furstenthal L, Hsu J, Kaiser B et al. (2000). The lore of the RINGs: substrate recognition and catalysis by ubiquitin ligases. Trends Cell Biol 10: 429–439.

    Article  CAS  Google Scholar 

  • Jarriault S, Brou C, Logeat F, Schroeter E, Kopan R, Israel A . (1995). Signalling downstream of activated mammalian Notch. Nature 377: 355–358.

    Article  CAS  Google Scholar 

  • Liu W-H, Lai M-Z . (2005). Deltex regulates T-cell activation by targeted degradation of active MEKK1. Mol Cell Biol 25: 1367–1378.

    Article  CAS  Google Scholar 

  • Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P et al. (1998). Human deltex is a conserved regulator of Notch signalling. Nat Genet 19: 74–78.

    Article  CAS  Google Scholar 

  • Matsuno K, Ito M, Hori K, Miyashita F, Suzuki S, Kishi N et al. (2002). Involvement of a proline-rich motif and RING-H2 finger of deltex in the regulation of Notch signaling. Development 129: 1049–1059.

    CAS  PubMed  Google Scholar 

  • Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakona S . (2005). Regulation of Notch signalling by non-visual beta-arrestin. Nat Cell Biol 7: 1191–1201.

    Article  Google Scholar 

  • Radtke F, Raj K . (2003). The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3: 756–767.

    Article  CAS  Google Scholar 

  • Sestan N, Artavanis-Tsakonas S, Rakic P . (1999). Contact-dependent inhibition of cortical neurite growth mediated by Notch signaling. Science 286: 741–746.

    Article  CAS  Google Scholar 

  • Struhl G, Adachi A . (1998). Nuclear access and action of Notch in vivo. Cell 93: 649–660.

    Article  CAS  Google Scholar 

  • Takebayashi K, Sasai Y, Sakai Y, Watanabe T, Nakanishi S, Kageyama R . (1994). Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. Negative autoregulation through the multiple N box elements. J Biol Chem 269: 5150–5156.

    CAS  PubMed  Google Scholar 

  • Thompson BJ, Jankovic V, Gao J, Buonamici S, Vest A, Lee JM et al. (2008). Control of hematopoietic stem cell quiescence by the E3 ubiquitin ligase Fbw7. J Exp Med 205: 1395–1408.

    Article  CAS  Google Scholar 

  • Weng AP, Ferrando AA, Lee W, Morris IV JP, Silverman LB, Sanchez-Irizarry C et al. (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science 306: 269–271.

    Article  CAS  Google Scholar 

  • Wilkin M, Tongngok P, Gensch N, Clemence S, Motoki M, Yamada K et al. (2008). Drosophila HOPS and AP-3 complex genes are required for a deltex-regulated activation of notch in the endosomal trafficking pathway. Dev Cell 15: 762–772.

    Article  CAS  Google Scholar 

  • Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A et al. (2001). SEL-10 is an inhibitor of Notch signaling that targets Notch for ubiquitin-mediated protein degradation. Mol Cell Biol 21: 7403–7415.

    Article  CAS  Google Scholar 

  • Zhang P, Yang Y, Zweidler-McKay PA, Hughes DPM . (2008). Critical role of Notch signaling in osteosarcoma invasion and metastasis. Clin Cancer Res 14: 2962–2969.

    Article  CAS  Google Scholar 

  • Zweidler-McKay P, Pear W . (2004). Notch and T cell malignancy. Semin Cancer Biol 14: 329–340.

    Article  CAS  Google Scholar 

  • Zweidler-McKay PA, He Y, Xu L, Rodriguez CG, Karnell FG, Carpenter AC et al. (2005). Notch signaling is a potent inducer of growth arrest and apoptosis in a wide range of B-cell malignancies. Blood 106: 3898–3906.

    Article  CAS  Google Scholar 

  • Zweifel M, Leahy D, Barrick D . (2005). Structure and Notch receptor binding of the tandem WWE domain of Deltex. Structure 13: 1599–1611.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Dr Tetsuo Sudo, Dr Anders Ström and Dr Iannis Aifantis for providing reagents, and to Dr Shufang Jia and Dr Wendy Fang for technical assistance. This work was supported by Physician Scientist Awards from UT MD Anderson Cancer Center to Dr D Hughes and Dr P Zweidler-McKay and by NIH Grant K08CA118730-04 to Dr Dennis Hughes. Dr P Zhang was supported by the Jori Zemel Children's Bone Cancer Foundation (www.JoriZemel.com) and Hope Street Kids Foundation (www.hopestreetkids.org).

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  1. Department of Pediatrics Research, Children's Cancer Hospital, University of Texas MD Anderson Cancer Center, Houston, TX, USA

    P Zhang, Y Yang, R Nolo, P A Zweidler-McKay & D P M Hughes

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  1. P Zhang
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Correspondence to D P M Hughes.

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Supplementary Information accompanies the paper on the Oncogene website

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Zhang, P., Yang, Y., Nolo, R. et al. Regulation of NOTCH signaling by reciprocal inhibition of HES1 and Deltex 1 and its role in osteosarcoma invasiveness. Oncogene 29, 2916–2926 (2010). https://doi.org/10.1038/onc.2010.62

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