The p53 tetramer bound to DNA
© 2009 Madhumalar Arumugam, A*STAR
In November 2009, more than 300 researchers gathered in a conference hall of the A*STAR Biopolis research complex in Singapore to learn of the latest insights into p53, one of the most important cancer-suppressor proteins so far discovered. The symposium, entitled ‘The UK–Singapore Symposium on p53: The Next 30 Years’, was jointly organized and sponsored by A*STAR, the British High Commission in Singapore and the A*STAR Bioinformatics Institute to mark the 30th anniversary of the discovery of p53.
Twenty speakers from the UK, Singapore and other countries gave presentations on how to elucidate the ever-more-complex mechanisms surrounding this single protein. All of the participants shared the confidence that every step brings them closer to inventing new therapeutic treatments, yet at the same time remain challenged by the new questions that continue to be raised as research progresses.
Back in 1979, six groups of molecular biologists, including David Lane, now chief scientist of A*STAR, separately reported a gene encoding p53 that binds to the large T-antigen of the oncogenic virus SV40. But its understanding as a ‘cancer-causing protein’ was challenged in 1990 when a mutation in p53 was confirmed in tumor cells but not in normal tissues. The role of p53 proved to be quite the opposite—it was actually ‘the guardian of the genome’, a transcriptional factor that regulates stress-inducing genes and which was mutated in more than half of all human cancers.
Surprises surrounding p53 have never stopped emerging. “The protein was thought to only be involved in tumor suppression but now has been showing involvement very dramatically in aging, fertility, metabolism and diabetes,” says Lane, who was also an organizer of the symposium. In the summer of 2009, p53 once again came into the spotlight following several papers suggesting strong similarities between the pathways for generating induced pluripotent stem (iPS) cells, which behave like stem cells, and the pathways for switching cells into cancers.
The complex nature of p53 has fascinated many scientists, with about 50,000 papers published to date. At the symposium, there were many active discussions on how to best exploit the findings linked to the protein, and the talks covered the full range of approaches: from classic molecular experiments using knockout mice, to genome-wide analyses for predictive pharmacology.
Sir David Lane, chief scientist, A*STAR
Gerald Evan of the University of California in San Francisco and the University of Cambridge talked about what Lane calls ‘cyclotherapy’—a method of activating p53 to stop cell divisions at a low level, effectively but temporarily arresting normal cell cycles while tumor cells keep proliferating. This concept could lead to the development of non-toxic drugs that can selectively target the cycling of tumor cells and kill them without causing severe side effects. So far, p53 has been a difficult target for drug design because of the frequent revision of its known pathways. Only one drug targeting p53 pathways has been clinically approved, but at least 12 candidates are in clinical testing.
Lane stresses the importance of introducing computational technologies, and has been working closely with Chandra Verma, leader of the Biomolecular Modeling and Design Division at the A*STAR Bioinformatics Institute. One of their main projects aims to investigate the interaction between p53 and Mdm2, an E3 ubiquitin ligase that binds with p53 as a negative regulator. Overexpression of Mdm2, along with other factors, can inactivate p53 in tumor cells. Inhibiting the interaction and reactivating p53 is one of the most important challenges in the development of new drugs.
At the symposium, Lane also presented an interesting genomic project implemented with Verma and others in 2009—the search for the origin of p53 and Mdm2. It is known that the p53 protein has been conserved from primitive invertebrates such as Placazoa to humans, but Mdm2 is absent in familiar model organisms such as the worm Caenorhabditis elegans and the fruit fly Drosophila melanogaster. The team discovered genes that look like Mdm2 in primitive invertebrates like the Placozoa and other arthropods like the deer tick, showing that Mdm2 is actually an ancient gene controlling p53 and suggesting that it has been lost by certain organisms. They said it was an exciting, one-week project. “I appreciate the atmosphere of intensity here in Singapore,” Lane says.
The A*STAR co-organizers of the symposium were David Lane, chief scientist and head of the newly established p53 Laboratory, and Chandra Verma of the Bioinformatics Institute.
