Abstract
The tumour suppressor p53 transcriptionally regulates a range of target genes that control cell growth and survival. Mutations of p53 have been implicated in the development of ∼50% of human cancers, including those instigated by exposure to mutagens. Although numerically rare, cancers can arise as a consequence of inherited mutations, such as in the Li–Fraumeni syndrome, which is caused by mutation of one p53 allele. Gene-targeted mice deficient for p53 have been generated to study this familial cancer syndrome. On a C57BL/6 background, p53-deficient mice develop primarily thymic lymphoma and more rarely sarcoma. Evasion of apoptosis is considered to be essential for neoplastic transformation. As proteins of the Bcl-2 family are the critical regulators of apoptosis, we investigated the role of the pro-survival members Bcl-2, Bcl-xL and Bcl-w in cancer development in p53+/− and p53−/− mice by testing whether ABT-737, a pharmacological inhibitor of these proteins, could prevent or delay tumourigenesis. Our studies showed that ABT-737 prophylaxis only caused a minor delay and reduction in γ-radiation-induced thymic lymphoma development in p53−/− mice, but this was accompanied by a concomitant increase in sarcoma. These data show that, collectively, Bcl-2, Bcl-xL and Bcl-w have only minor roles in thymic lymphoma development elicited by defects in p53, and this may indicate that Mcl-1 and/or A1 may feature more prominently in this process.
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Abbreviations
- qRT-PCR:
-
quantitative PCR
- FACS:
-
fluorescence-activated cell sorting
- FCS:
-
fetal calf serum
- DMSO:
-
dimethyl sulphoxide
- BSS:
-
balanced salt solution
- CL:
-
cell line
- wt:
-
wild type
- Ctrl:
-
control value
- WBC:
-
white blood cell count
- Eμ-myc/rv-bcl-2:
-
Eμ-myc B lymphoma cells that had been retrovirally transduced with a Bcl-2 expression construct
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Acknowledgements
We thank Abbott Laboratories and Genentech Inc. for providing us with ABT-737; Dr. T Jacks for p53-deficient mice; Drs. LA O’Reilly and DC Huang, and Mr. ARD Delbridge, for advice and reagents; K McKenzie, G Siciliano, N Iannarella, L Reid and K Vella for expert animal care; B Helbert and C Young for genotyping; J Corbin for automated blood analysis; E Tsui, V Babo, K Weston, Y Hoang and S Hasanein for histology, and D Quilici, T Nikolaou and G Thomas for γ-irradiation. This work was supported by grants and fellowships from the Cancer Council of Victoria (to PNK), the National Health and Medical Research Council (Program Grant no. 461221; NHMRC Australia Fellowship), the NIH (CA43540) and the Leukemia and Lymphoma Society (SCOR Grant no. 7413), University of Melbourne International Research Scholarship, University of Melbourne International Fee Remission Scholarship, Cancer Therapeutics CRC Top-up Scholarship (last three to SG) and operational infrastructure grants through the Australian Government IRISS and the Victorian State Government OIS.
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Grabow, S., Waring, P., Happo, L. et al. Pharmacological blockade of Bcl-2, Bcl-xL and Bcl-w by the BH3 mimetic ABT-737 has only minor impact on tumour development in p53-deficient mice. Cell Death Differ 19, 623–632 (2012). https://doi.org/10.1038/cdd.2011.133
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DOI: https://doi.org/10.1038/cdd.2011.133
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