International Hermelin Brain Tumor Center Symposium on Apoptosis

Henry Ford Hospital, Detroit, MI,USA 4th and 5th April 2003

Apoptosis can be said, like many facets of cancer, to start with p53. This is not meant to imply that p53 plays a mechanistic role in every cell death event, but rather that the loss of its function in malignant cells profoundly alters their propensity to undergo apoptosis. This has been elegantly demonstrated in mouse models, such as the one for choroid plexus carcinoma, where the major consequence of p53 loss early in the evolution of tumors is the reduced sensitivity to spontaneous apoptosis.² Erwin Van Meir from the Department of Neurosurgery at Emory University, Atlanta, presented an interesting study investigating whether changes in apoptotic regulation were also an important element of p53-loss-driven gliomagenesis in humans. He presented a glioma patient with a germline p53 mutation, R283 H, in which the sequential inactivation of p53 had been examined in detail.³ While most commonly a point mutation in p53 is followed by loss of heterozygosity (LOH) eliminating the remaining wild-type allele, no LOH was detected in this patient. Instead, two mutant alleles of p53 were identified in the recurrent tumor: the one present in the germ line, which had also acquired a second mutation at R267W, and the other allele, which had suffered a different mutation, E258D. p53 transcriptional assays in yeast, used to trace the evolution of the tumor, surprisingly showed that the acquisition of the second mutation in the allele carrying R283 H preceded the mutation in the remaining wild-type allele. Once all three mutations were present, this led to rapid clonal dominance of p53^{R283 H R267W, E258D} cells. The need for a second point mutation in the R283 H allele was explained by the observation that the R283 H mutant retained its ability to activate the CDKN1A promoter and so inhibit the cell cycle. Interestingly, R283 H was significantly compromised in its induction of the bax promoter, suggesting an early and important contribution in a reduction in apoptosis to the survival of cells that may be proliferating abnormally.

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