Another key to the p53 door
scientists who believe it plays such a key role in preventing
cancer onset that it opens up a range of different targeting
options for multiple types of cancer.
Researchers have discovered that the transcription factor Yin Yang 1 (YY1) is a novel regulator of the tumour suppressor p53, which is inactivated in at least half of all human cancers.
The p53 transcription factor plays a vital role in preventing cancer onset, by stimulating cells to commit suicide when chemicals or UV exposure damages their DNA. This control mechanism is deactivated in about 50 per cent of all human tumours - usually because the p53 protein itself is dysfunctional - so this pathway has been dissected by researchers for years, in the hope of finding an effective drug that will work in a broad range of cancer patients.
Because YY1 prevents p53 from removing pre-cancerous cells, YY1 represents a candidate for a source of p53-inactivating mutations, as well as a potential new target for future therapies.
According to a paper published in the August 4 issue of PNAS, researchers at the Ludwig Institute for Cancer Research (LICR) discovered that YY1 regulates p53 at multiple levels. First, YY1 uses the novel mechanism of causing Mdm2, a key oncogene that marks proteins for degradation, to have an enhanced interaction with p53, decreasing the amount of p53 in the cell
7 per cent of cancers are characterised by an overexpression of MDM2, although it is more common in certain types of malignancy such as sarcomas, with an incidence of 20-30 per cent.
YY1 also directly blocks p53's interaction with its cofactors, such that p53 can no longer act as a transcription factor to cause cell suicide in response to DNA damage.
Dr. Johan Ericsson, the senior author of the study said: "In terms of possible therapies for the future, YY1's regulation of p53 at different levels means that we have new, different targeting options."
"We know that we can use small molecules to prevent transcription factors from interacting with other proteins, so we can consider blocking YY1's direct interaction with p53 as a therapy option. We can also think about ways of disrupting the Mdm2 and YY1 interaction, and so prevent the indirect inhibition of p53."
Ericsson added: "YY1 interacts with several transcription factors involved in cancer, for example, Myc and Notch, and now we know it also regulates p53."
"No-one has yet looked at mutations in YY1, but the fact that it is associated with so many proteins implicated in tumorigenesis, suggests to me that YY1 could be a lot more important than anyone ever realized."
