Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation

M. Calao, E. O. Sekyere, H. J. Cui, B. B. Cheung, W. D. Thomas, J. Keating, J. B. Chen, A. Raif, K. Jankowski, N. P. Davies, M. V. Bekkum, B. Chen, O. Tan, T. Ellis, M. D. Norris, M. Haber, E. S. Kim, J. M. Shohet, T. N. Trahair, T. LiuB. J. Wainwright, H. F. Ding, G. M. Marshall

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Abstract

Embryonal cancer can arise from postnatally persistent embryonal remnant or rest cells, which are uniquely characterized by the absence of p53 mutations. Perinatal overexpression of the MycN oncoprotein in embryonal cancer precursor cells causes postnatal rests, and later tumor formation through unknown mechanisms. However, overexpression of Myc in adult tissues normally activates apoptosis and/or senescence signals as an organismal defense mechanism against cancer. Here, we show that perinatal neuroblastoma precursor cells exhibited a transiently diminished p53 response to MycN oncoprotein stress and resistance to trophic factor withdrawal, compared with their adult counterpart cells from the TH-MYCN +/+ transgenic mouse model of neuroblastoma. The adult stem cell maintenance factor and Polycomb group protein, Bmi1 (B-cell-specific Moloney murine leukemia virus integration site), had a critical role at neuroblastoma initiation in the model, by repressing p53 responses in precursor cells. We further show in neuroblastoma tumor cells that Bmi1 could directly bind p53 in a complex with other Polycomb complex proteins, Ring1A or Ring1B, leading to increased p53 ubiquitination and degradation. Repressed p53 signal responses were also seen in precursor cells for other embryonal cancer types, medulloblastoma and acute lymphoblastic leukemia. Collectively, these date indicate a general mechanism for p53 inactivation in some embryonal cell types and consequent susceptibility to MycN oncogenesis at the point of embryonal tumor initiation.

Original languageEnglish (US)
Pages (from-to)3616-3626
Number of pages11
JournalOncogene
Volume32
Issue number31
DOIs
StatePublished - Aug 1 2013

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Protein Stability
Germ Cell and Embryonal Neoplasms
Oncogene Proteins
Neuroblastoma
Neoplasms
Polycomb-Group Proteins
Virus Integration
Moloney murine leukemia virus
Medulloblastoma
Adult Stem Cells
Stem Cell Factor
Ubiquitination
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Transgenic Mice
Carcinogenesis
B-Lymphocytes
Maintenance
Apoptosis
Mutation

Keywords

  • Bmi1
  • MYCN
  • apoptosis
  • medulloblastoma
  • neuroblastoma
  • p53

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Calao, M., Sekyere, E. O., Cui, H. J., Cheung, B. B., Thomas, W. D., Keating, J., ... Marshall, G. M. (2013). Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation. Oncogene, 32(31), 3616-3626. https://doi.org/10.1038/onc.2012.368

Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation. / Calao, M.; Sekyere, E. O.; Cui, H. J.; Cheung, B. B.; Thomas, W. D.; Keating, J.; Chen, J. B.; Raif, A.; Jankowski, K.; Davies, N. P.; Bekkum, M. V.; Chen, B.; Tan, O.; Ellis, T.; Norris, M. D.; Haber, M.; Kim, E. S.; Shohet, J. M.; Trahair, T. N.; Liu, T.; Wainwright, B. J.; Ding, H. F.; Marshall, G. M.

In: Oncogene, Vol. 32, No. 31, 01.08.2013, p. 3616-3626.

Research output: Contribution to journalArticle

Calao, M, Sekyere, EO, Cui, HJ, Cheung, BB, Thomas, WD, Keating, J, Chen, JB, Raif, A, Jankowski, K, Davies, NP, Bekkum, MV, Chen, B, Tan, O, Ellis, T, Norris, MD, Haber, M, Kim, ES, Shohet, JM, Trahair, TN, Liu, T, Wainwright, BJ, Ding, HF & Marshall, GM 2013, 'Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation', Oncogene, vol. 32, no. 31, pp. 3616-3626. https://doi.org/10.1038/onc.2012.368
Calao, M. ; Sekyere, E. O. ; Cui, H. J. ; Cheung, B. B. ; Thomas, W. D. ; Keating, J. ; Chen, J. B. ; Raif, A. ; Jankowski, K. ; Davies, N. P. ; Bekkum, M. V. ; Chen, B. ; Tan, O. ; Ellis, T. ; Norris, M. D. ; Haber, M. ; Kim, E. S. ; Shohet, J. M. ; Trahair, T. N. ; Liu, T. ; Wainwright, B. J. ; Ding, H. F. ; Marshall, G. M. / Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation. In: Oncogene. 2013 ; Vol. 32, No. 31. pp. 3616-3626.
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