“Millions of our cells die through apoptosis every day” – Apoptotic signalling research group at the IMIM

Gabriel Gil has directed the Apoptotic Signalling research group of the IMIM since 2000. Apoptosis, or programmed cell death, is a physiological process with an essential role both during development and in the adult organism. “The epithelium of our body renews each day, in such a way that millions of cells die through apoptosis daily. Self-reactive lymphocytes, which recognise the body’s own antigens and which can attack it, are also eliminated by apoptosis”, explains the researcher. The absence of apoptosis, on the other hand, is a trait characteristic of the majority of tumours. “Apoptosis is, in fact, a safeguard mechanism existing in all cells and which ensures that if the DNA becomes damaged and impossible or very difficult to repair, the cell will die, meaning this genetic error will not be passed on. If this mechanism does not work, the errors are perpetuated, as happens in cancer.”

A new Cyclin

Soon after he set up his group, Gil identified a new protein, Cyclin O, which appears to be implicated in the detection of DNA lesions. They believe that it could be the link between the detection of these lesions and the initiation of the apoptotic mechanism. Since then, this protein has been the focus of their research and they have discovered that it is overexpressed in various cancers, especially of the colon and bladder. “We work with pathologists, oncologists, dermatologists, and urologists from the Hospital del Mar in order to study, in patient samples, why Cyclin O is not regulated in these cases and what advantages this offers the tumour”, says Gil.

To understand how Cyclin O works on a molecular level, the group uses different biochemical and molecular biology techniques. They also work with animal models and have generated the first mouse knockout (KO) for Cyclin O, i.e. a mouse which does not express this protein.

Cyclin O is expressed only when the cell becomes damaged. Over the past years the group has discovered some of the external stimuli which provoke apoptosis via Cyclin O, such as DNA damage or endoplasmic reticulum stress through the accumulation of badly folded proteins. In the case of lymphocytes, glucocorticoids also induce apoptosis, which makes them useful against inflammation, explains the head of the group.

Alongside the patients 

Recently the group has discovered that Cyclin O can regulate ATM, a protein essential for the detection of DNA damage. ATM mutations are the cause of ataxia telangiectasia, a very rare but very serious disease which causes immunodeficiency, neurological problems and a greater risk of developing tumours. Gil received a grant from the Marató de TV3 to study the role of Cyclin O in this disease. Recently, the Spanish association for families with ataxia telangiectasia (AEFAT) invited the scientist together with Oskar Fernández-Capetillo, a researcher from the CNIO and an expert in the field of ATM, to present their research to the families of those affected. The researchers were then asked to help in preparing a simple and standardised molecular diagnostic method for the disease.

“The problem is that there is no established molecular diagnostic procedure, and the complexity of the gene and the low frequency of the disease make it commercially unattractive to develop one. But being able to diagnose it within the first year of life may greatly improve the results of the palliative treatments which these children currently receive”, emphasises the head of the group. “In addition, it would be very useful to identify the carriers of the mutated gene, who, even though they do not suffer the disease, also have a higher probability of developing tumours”.

This article was published in the El·lipse publication of the PRBB

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