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., Lui, T., Wainwright, B. J., Ding, H. F. and 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. doi:10.1038/onc.2012.368


Author 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.
Lui, T.
Wainwright, B. J.
Ding, H. F.
Marshall, G. M.
Title Direct effects of Bmi1 on p53 protein stability inactivates oncoprotein stress responses in embryonal cancer precursor cells at tumor initiation
Journal name Oncogene   Check publisher's open access policy
ISSN 0950-9232
1476-5594
Publication date 2013-08-01
Year available 2012
Sub-type Article (original research)
DOI 10.1038/onc.2012.368
Volume 32
Issue 31
Start page 3616
End page 3626
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Collection year 2013
Language eng
Formatted 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.
Keyword Bmi1
p53
MYCN
Neuroblastoma
Medulloblastoma
Apoptosis
MYC transgenic mice
Stem-cells
In-vivo
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online 20 August 2012

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
Institute for Molecular Bioscience - Publications
 
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Created: Fri, 16 Nov 2012, 14:12:25 EST by Susan Allen on behalf of Institute for Molecular Bioscience