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.

  • Short Communication
  • Published:

Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation

Oncogene volume 27, pages 3339–3344 (2008)Cite this article

Abstract

In neuroblastoma cells, retinoic acid induces cell cycle arrest and differentiation through degradation of the F-box protein, Skp2, and stabilization of cyclin-dependent kinase inhibitor, p27. However, the mechanism responsible for retinoic acid-mediated Skp2 destabilization is unknown. Since Skp2 is degraded by anaphase-promoting complex (APC)Cdh1, here we studied whether retinoic acid promotes differentiation of human SH-SY5Y neuroblastoma cells by modulating Cdh1. We found that retinoic acid induced the nuclear accumulation of Cdh1 that paralleled Skp2 destabilization and p27 accumulation. The mRNA and protein abundance of Rae1—a nuclear export factor that limits APCCdh1 activity in mitosis—decreased upon retinoic acid-induced inhibition of neuroblastoma cell proliferation. Furthermore, either Rae1 overexpression or Cdh1 inhibition promoted Skp2 accumulation, p27 destabilization and prevented retinoic acid-induced cell cycle arrest and differentiation. Conversely, inhibition of Rae1 accelerated retinoic acid-induced differentiation. Thus, retinoic acid downregulates Rae1, hence facilitating APCCdh1-mediated Skp2 degradation leading to the arrest of cell cycle progression and neuroblastoma differentiation.

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

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  • Almeida A, Bolaños JP, Moreno S . (2005). Cdh1/Hct1-APC is essential for the survival of postmitotic neurons. J Neurosci 25: 8115–8121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bashir T, Dorrello NV, Amador V, Guardavaccaro D, Pagano M . (2004). Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligase. Nature 428: 190–193.

    Article  CAS  PubMed  Google Scholar 

  • Binne UK, Classon MK, Dick FA, Wei W, Rape M, Kaelin Jr WG et al. (2007). Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit. Nat Cell Biol 9: 225–232.

    Article  CAS  PubMed  Google Scholar 

  • Bloom J, Pagano M . (2003). Deregulated degradation of the cdk inhibitor p27 and malignant transformation. Semin Cancer Biol 13: 41–47.

    Article  CAS  PubMed  Google Scholar 

  • Blower MD, Nachury M, Heald R, Weis K . (2005). A Rae1-containing ribonucleoprotein complex is required for mitotic spindle assembly. Cell 121: 223–234.

    Article  CAS  PubMed  Google Scholar 

  • Borriello A, Cucciolla V, Criscuolo M, Indaco S, Oliva A, Giovane A et al. (2006). Retinoic acid induces p27Kip1 nuclear accumulation by modulating its phosphorylation. Cancer Res 66: 4240–4248.

    Article  CAS  PubMed  Google Scholar 

  • Brummelkamp TR, Bernards R, Agami R . (2002). A system for stable expression of short interfering RNAs in mammalian cells. Science 296: 550–553.

    CAS  PubMed  Google Scholar 

  • Carrano AC, Eytan E, Hershko A, Pagano M . (1999). SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27. Nat Cell Biol 1: 193–199.

    Article  CAS  PubMed  Google Scholar 

  • Clagett-Dame M, McNeill EM, Muley PD . (2006). Role of all-trans retinoic acid in neurite outgrowth and axonal elongation. J Neurobiol 66: 739–756.

    Article  CAS  PubMed  Google Scholar 

  • Dow R, Hendley J, Pirkmaier A, Musgrove EA, Germain D . (2001). Retinoic acid-mediated growth arrest requires ubiquitylation and degradation of the F-box protein Skp2. J Biol Chem 276: 45945–45951.

    Article  CAS  PubMed  Google Scholar 

  • Encinas M, Iglesias M, Liu Y, Wang H, Muhaisen A, Cena V et al. (2000). Sequential treatment of SH-SY5Y cells with retinoic acid and brain-derived neurotrophic factor gives rise to fully differentiated, neurotrophic factor-dependent, human neuron-like cells. J Neurochem 75: 991–1003.

    Article  CAS  PubMed  Google Scholar 

  • Gieffers C, Peters BH, Kramer ER, Dotti CG, Peters JM . (1999). Expression of the CDH1-associated form of the anaphase-promoting complex in postmitotic neurons. Proc Natl Acad Sci USA 96: 11317–11322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hsu JY, Reimann JDR, Sørensen CS, Lukas J, Jackson PK . (2002). EF2-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC-Cdh1. Nat Cell Biol 4: 358–366.

    Article  CAS  PubMed  Google Scholar 

  • Jeganathan KB, Malureanu L, van Deursen JM . (2005). The Rael-Nup98 complex prevents aneuploidy by inhibiting securin degradation. Nature 438: 1036–1039.

    Article  CAS  PubMed  Google Scholar 

  • Konishi Y, Stegmüller J, Matsuda T, Bonni S, Bonni A . (2004). Cdhl-APC controls axonal growth and patterning in the mammalian brain. Science 303: 1026–1030.

    Article  CAS  PubMed  Google Scholar 

  • Lasorella A, Stegmuller J, Guardavaccaro D, Liu G, Carro MS, Rothschild G et al. (2006). Degradation of Id2 by the anaphase-promoting complex couples cell cycle exit and axonal growth. Nature 442: 471–474.

    Article  CAS  PubMed  Google Scholar 

  • Maden M . (2002). Retinoid signalling in the development of the central nervous system. Nat Rev Neurosci 3: 843–853.

    Article  CAS  PubMed  Google Scholar 

  • Matthay MA . (1999). Conference summary: acute lung injury. Chest 116: 119S–126S.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura M, Matsuo T, Stauffer J, Neckers L, Thiele CJ . (2003). Retinoic acid decreases targeting of p27 for degradation via an N-myc-dependent decrease in p27 phosphorylation and an N-myc-independent decrease in Skp2. Cell Death Differ 10: 230–239.

    Article  CAS  PubMed  Google Scholar 

  • Nakayama K, Nagahama H, Minamishima YA, Miyake S, Ishida N, Hatakeyama S et al. (2004). Skp2-mediated degradation of p27 regulates progression into mitosis. Dev Cell 6: 661–672.

    Article  CAS  PubMed  Google Scholar 

  • Ohtsuka T, Ryu H, Minamishima YA, Macip S, Sagara J, Nakayama KI et al. (2004). ASC is a Bax adaptor and regulates the p53-Bax mitochondrial apoptosis pathway. Nat Cell Biol 6: 121–128.

    Article  CAS  PubMed  Google Scholar 

  • Reimann JD, Freed E, Hsu JY, Kramer ER, Peters JM, Jackson PK . (2001). Emi1 is a mitotic regulator that interacts with Cdc20 and inhibits the anaphase promoting complex. Cell 105: 645–655.

    Article  CAS  PubMed  Google Scholar 

  • Reynolds CP, Matthay KK, Villablanca JG, Maurer BJ . (2003). Retinoid therapy of high-risk neuroblastoma. Cancer Lett 197: 185–192.

    Article  CAS  PubMed  Google Scholar 

  • Sheaff RJ, Groudine M, Gordon M, Roberts JM, Clurman BE . (1997). Cyclin E-CDK2 is a regulator of p27Kip1. Genes Dev 11: 1464–1478.

    Article  CAS  PubMed  Google Scholar 

  • Sutterluty H, Chatelain E, Marti A, Wirbelauer C, Senften M, Muller U et al. (1999). p45SKP2 promotes p27Kip1 degradation and induces S phase in quiescent cells. Nat Cell Biol 1: 207–214.

    Article  CAS  PubMed  Google Scholar 

  • Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG . (2004). Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex. Nature 428: 194–198.

    Article  CAS  PubMed  Google Scholar 

  • Zancai P, Dal Col J, Piccinin S, Guidoboni M, Cariati R, Rizzo S et al. (2005). Retinoic acid stabilizes p27Kip1 in EBV-immortalized lymphoblastoid B cell lines through enhanced proteasome-dependent degradation of the p45Skp2 and Cks1 proteins. Oncogene 24: 2483–2494.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms Mónica Resch for her excellent technical assistance; and Prof M Pagano (Department of Pathology, New York University School of Medicine and NYU Cancer Institute, USA) for generously providing wild-type Skp2 cDNA. JC is recipient of a fellowship from the Universidad de Salamanca. SM is funded by AECC Foundation and BFU2005-03195. JPB is funded by SAF2007-61492, CONSOLIDER, SA066A07 and Red Terapia Celular-ISCIII. AA is funded by the Fondo de Investigación Sanitaria (FIS06/0794) and the Junta de Castilla-León (SA082A05). This work was mainly funded by FIS06/0794.

Author information

Authors and Affiliations

  1. Unidad de Investigación, Hospital Universitario de Salamanca, Instituto de Estudios de Ciencias de la Salud de Castilla y León, Salamanca, Spain

    J Cuende & A Almeida

  2. Departamento de Bioquímica y Biología Molecular, Instituto de Neurociencias de Castilla y León, Universidad de Salamanca, Salamanca, Spain

    J Cuende, J P Bolaños & A Almeida

  3. Instituto de Biología Molecular y Celular del Cancer, Consejo Superior de Investigaciones Científicas, Universidad de Salamanca, Salamanca, Spain

    S Moreno

Authors
  1. J Cuende
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. S Moreno
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. J P Bolaños
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Almeida
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to A Almeida.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cuende, J., Moreno, S., Bolaños, J. et al. Retinoic acid downregulates Rae1 leading to APCCdh1 activation and neuroblastoma SH-SY5Y differentiation. Oncogene 27, 3339–3344 (2008). https://doi.org/10.1038/sj.onc.1210987

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1210987

Keywords

This article is cited by

Search

Advanced search

Quick links