UHN UT University of Toronto University Health Network


 

Investigating the role of p53 oligomerization on cell fate decisions and the clinical consequences of p53 mutations

 

Lab Members: Nicholas Fischer

Mutations in the oligomerization domain of p53 are genetically linked to cancer susceptibility in Li-Fraumeni Syndrome. These mutations typically alter the oligomeric state of p53 and impair its transcriptional activity. Activation of p53 through tetramerization is required for its tumor suppressive function by inducing transcriptional programs that lead to cell fate decisions such as cell cycle arrest or apoptosis. How p53 chooses between these cell fate outcomes remains unclear. Here, we use 5 oligomeric variants of p53, including 2 novel p53 constructs, that yield either monomeric, dimeric or tetrameric forms of p53 and demonstrate that they induce distinct cellular activities and gene expression profiles that lead to different cell fate outcomes. We report that dimeric p53 variants are cytostatic and can arrest cell growth, but lack the ability to trigger apoptosis in p53-null cells. In contrast, p53 tetramers induce rapid apoptosis and cell growth arrest, while a monomeric variant is functionally inactive, supporting cell growth. In particular, the expression of pro-arrest CDKN1A and pro-apoptotic P53AIP1 genes are important cell fate determinants that are differentially regulated by the oligomeric state of p53. This study suggests that the most abundant oligomeric species of p53 present in resting cells, namely p53 dimers, neither promote cell growth or cell death and that shifting the oligomeric state equilibrium of p53 in cells toward monomers or tetramers is a key parameter in p53-based cell fate decisions (1).

We are currently investigating the biochemical and clinical consequences of p53 mutations.

Figure 1. p53-mediated tumor suppression is controlled by its oligomeric state and requires the assembly of tetramers for rapid induction of apoptotic cell death. (A) Dead cell populations (PI stained) from cell death analysis by fluorescence activated cell sorting of H1299 p53-null cells expressing p53 oligomeric variants (mean ± SD (n = 3), ***p ≤ 0.001). (B) Cell cycle analysis of H1299 cells expressing p53 oligomeric variants. (C) Schematic drawing of the major cell fate decisions mediated by p53 oligomerization status.

 

 

Selected References

1) Fischer NW, Prodeus A, Malkin D, Gariépy J. (2016) p53 oligomerization status modulates cell fate decisions between growth, arrest and apoptosis. Cell Cycle, In Press.

2) Samuel N, Wilson G, Id Said B, Pan A, Deblois G, Fischer NW, Alexandrova R, Casallo G, Paton T, Lupien M, Gariepy J, Merico D, Hudson TJ, Malkin D. (2016) Transcriptome-wide characterization of the endogenous miR-34A-p53 tumor suppressor network. Oncotarget, In Press.

3) Poon GMK, Brokx RD, Sung M, Gariépy J. (2007) Tandem dimerization of the human p53 tetramerization domain stabilizes a primary dimer intermediate and dramatically enhances its oligomeric stability. J Mol Biol, 365(4):1217-1231.

4) Brokx RD, Bolewska-Pedyczak E, Gariépy J. (2003) A Stable Human p53 Heterotetramer Based on Constructive Charge Interactions within the Tetramerization Domain. J Biol Chem, 278(4): 2327-2332. BROCKX1

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