p53, the Cellular Gatekeeper for Growth and Division

Whether and how human tumours are genetically unstable has been debated for decades. There is now evidence that most cancers may indeed be genetically unstable, but that the instability exists at two distinct levels. In a small subset of tumours, the instability is observed at the nucleotide level and results in base substitutions or deletions or insertions of a few nucleotides. In most other cancers, the instability is observed at the chromosome level, resulting in losses and gains of whole chromosomes or large portions thereof. Recognition and comparison of these instabilities are leading to new insights into tumour pathogenesis.

Genetic instabilities in human cancers

As the tale of p53 unfolds, it becomes ever more intriguing. Although our understanding of the critical and complex roles played by p53 is progressing rapidly, new findings continue to pose new paradoxes. Here we present some of these recent advances in p53 research and discuss how they either shed light on or add to the complexities of p53. Therefore, we only briefly summarize some of the key developments leading to our current state of knowledge. For further information, the reader is referred to several excellent reviews that have focused on p53 research (see Donehower and Bradley 1993; Levine 1993; Greenblatt et al. 1994; Oren 1994; Prives 1994; Kinzler and Vogelstein 1996).

/pdf/p53-puzzle-and-paradigm-fhbzz71yci.pdf

p53: puzzle and paradigm.

The MDM2 oncoprotein is a cellular inhibitor of the p53 tumor suppressor in that it can bind the transactivation domain of p53 and downregulate its ability to activate transcription. In certain cancers, MDM2 amplification is a common event and contributes to the inactivation of p53. The crystal structure of the 109-residue amino-terminal domain of MDM2 bound to a 15-residue transactivation domain peptide of p53 revealed that MDM2 has a deep hydrophobic cleft on which the p53 peptide binds as an amphipathic alpha helix. The interface relies on the steric complementarity between the MDM2 cleft and the hydrophobic face of the p53 alpha helix and, in particular, on a triad of p53 amino acids-Phe19, Trp23, and Leu26-which insert deep into the MDM2 cleft. These same p53 residues are also involved in transactivation, supporting the hypothesis that MDM2 inactivates p53 by concealing its transactivation domain. The structure also suggests that the amphipathic alpha helix may be a common structural motif in the binding of a diverse family of transactivation factors to the TATA-binding protein-associated factors.

https://science.sciencemag.org/content/sci/274/5289/948.full.pdf

Structure of the MDM2 oncoprotein bound to the p53 tumor suppressor transactivation domain.

p63, a p53 homolog at 3q27-29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities.

Human pancreatic cancer develops in association with an acquired genomic instability, but the events that lead to instability are difficult to investigate because they occur sporadically and unpredictably. The elastase-SV40 T antigen transgenic mouse model of pancreatic adenocarcinoma reproducibly proceeds through a diploid --> tetraploid --> multiple aneuploid sequence of genetic abnormalities. We investigated the relationship between inactivation of p53 and development of tetraploidy in this model. Because T antigen inactivates p53 by forming a stable complex with it, we used multiparameter flow cytometry to assess p53 expression in pancreatic samples of transgenic and control mice between 8 and 24 days of age. On day 18, a cell cycle-specific inactivation of p53 developed between diploid G, and S phase and was associated with the appearance of a cycling tetraploid cell population that had p53 protein overexpression in both G1- and S-phase cells. Cytogenetic analysis of pancreatic samples confirmed the development of a tetraploid cell population. Inactivation of p53 in diploid cells of the transgenic pancreas is followed by the development of a tetraploid cell population. We have shown previously that this tetraploid intermediate is predisposed to progression to aneuploidy because it has abnormal mitotic poles. Therefore, our results suggest that inactivation of p53 by T antigen leads to formation of a tetraploid cell intermediate that is predisposed to chromosome segregation abnormalities and the development of multiple aneuploid cell populations.

Inactivation of p53 and the Development of Tetraploidy in the Elastase-SV40 T Antigen Transgenic Mouse Pancreas

Cell cycle checkpoints enhance genetic fidelity by causing arrest at specific stages of the cell cycle when previous events have not been completed. The tumor suppressor p53 has been implicated in a G1 checkpoint. To investigate whether p53 also participates in a mitotic checkpoint, cultured fibroblasts from p53-deficient mouse embryos were exposed to spindle inhibitors. The fibroblasts underwent multiple rounds of DNA synthesis without completing chromosome segregation, thus forming tetraploid and octaploid cells. Deficiency of p53 was also associated with the development of tetraploidy in vivo. These results suggest that murine p53 is a component of a spindle checkpoint that ensures the maintenance of diploidy.

https://science.sciencemag.org/content/sci/267/5202/1353.full.pdf

A p53-Dependent Mouse Spindle Checkpoint

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Inactivation of p53 and the Development of Tetraploidy in the Elastase-SV40 T Antigen Transgenic Mouse Pancreas

A p53-Dependent Mouse Spindle Checkpoint