Saturday, May 10, 2008

p53 gene and it's role in cancer

Ironically, death is critical to life.

Apoptosis is the programmed death of cells that are irretrievably damaged or at the end of their useful life. The process is essential for organisms to develop and survive by regenerating new cells. In cancer, this process goes awry because mutations allow cells to divide and proliferate uncontrollably rather than dying, so a tumour mass is formed.

Mutations can occur by addition, deletion or inactivation. Inactivation of p53, for example, can lead to the development of different types of cancer. Although scientists have long known that p53 inactivation plays a central role in the development of cancer, little was known about whether p53 inactivation played a role in maintaining cancers. It was also unclear whether switching p53 back on in tumour cells would have any therapeutic effect.

In 2007, researchers at the Howard Hughes Medical Institute demonstrated that inactivating the p53 gene is necessary for maintaining tumour survival. Conversely, reactivating the p53 gene in mice caused blood, bone and liver tumours to self destruct. The p53 protein is called the “guardian of the genome” because it triggers the suicide of cells with damaged DNA. Cancers can, however, mutate to circumvent p53 reactivation.

It is now known that in most cancer cases, the P53 gene is damaged or switched off, but Scottish researchers found they could reboot it. Biological compounds called tenovins were used to turn off certain enzymes which act as switches and control p53. The compounds were initially selected for study because they induced the required effect on whole cells as opposed to the use of purified proteins. The findings indicate that improved tenovin derivatives may have the potential to stop tumours and that their ability to switch on P53 contributes to this. Tenovins work by inhibiting sirtuins. This may facilitate further optimisation of the compounds in development for inactivating the cancer.

Note: GSK recently purchased Sirtris, a biotechnology company focused on sirtuin research

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