Poster Presentation 25th Lorne Cancer Conference 2013

A novel DNA damage-induced apoptotic pathway cooperates with p53 to enforce tumour suppression (#155)

Alex RD Delbridge 1 2 , Clare Scott 1 2 , Philippe Bouillet 1 2 , Andreas Strasser
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Medical Biology, University of Melbourne, Melbourne, Victoria, Australia

Loss of even a single allele of p53 results in a profound predisposition to tumour development in both mice and humans1234.  Furthermore loss of p53 pathway activity represents a significant barrier to achieving a successful cancer treatment outcome in the clinic.  p53’s potent tumour suppressor activity was presumed to relate to its ability to induce apoptosis under conditions of oncogenic stress, however recent studies have clearly demonstrated that activation of downstream pro-apoptotic proteins by p53 is not required for efficient tumour suppression56 7

We sought to gain further insight into mechanisms of tumour suppression by investigating apoptotic pathways that are activated independently of p53.  Specifically we have investigated whether DNA damage provokes activation of pro-apoptotic pathways capable of negating expansion of nascent pre-neoplastic cells and killing of fully transformed tumour cells.

In these experiments we identified a novel DNA damage-induced apoptotic pathway that is independent of p53 but activates the pro-apoptotic BCL-2 family member, BIM.  In the absence of p53, BIM is required for efficient induction of DNA damage-induced apoptosis in both normal and transformed cells and enforces tumour suppression in vivo.  These findings provide insight into the mechanisms that underpin lymphomagenesis and have important implications for the treatment of lymphoma in the clinic.

  1. Donehower. The p53-deficient mouse: a model for basic and applied cancer studies. Semin Cancer Biol (1996) vol. 7 (5) pp. 269-78
  2. Jacks et al. Tumor spectrum analysis in p53-mutant mice. Curr Biol (1994) vol. 4 (1) pp. 1-7
  3. Malkin et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science (1990) vol 250 pp. 1233–1238.
  4. Srivastava et al. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature (1990) vol 348, pp 747–749
  5. Brady et al. Distinct p53 Transcriptional Programs Dictate Acute DNA-Damage Responses and Tumor Suppression. Cell (2011) vol. 145 (4) pp. 571-583
  6. Li et al. Tumor Suppression in the Absence of p53-Mediated Cell-Cycle Arrest, Apoptosis, and Senescence. Cell (2012) vol. 149 (6) pp. 1269-1283
  7. Michalak et al. In several cell types tumour suppressor p53 induces apoptosis largely via Puma but Noxa can contribute. Cell Death Differ (2008) vol. 15 (6) pp. 1019-29