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CNIO Publications, Year 2015

Developmental Cell

CNIO experts identify an oncogene regulated by nutrients

Madrid, 13 April, 2015

In response to nutrient excess, the MCRS1 protein acts as a ‘switch’ for mTOR, a protein that is altered in cancer, diabetes and disorders associated with ageing

The results correlate with increased MCRS1 protein levels in samples taken from patients with colorectal cancer

Blocking this protein may prove to be an effective treatment for cancer or other diseases associated with mTOR alterations

Scientists from the Growth Factors, Nutrients and Cancer Group at the Spanish National Cancer Research Center (CNIO), led by Nabil Djouder, have discovered that the MCRS1 protein, in response to an excess of nutrients, induces an increase in the activity of mTOR (the mammalian/mechanistic Target of Rapamycin); a protein that is altered in human diseases such as cancer and diabetes, processes associated with ageing, as well as in certain cardiovascular and neurodegenerative pathologies. The finding, published in the journal Developmental Cell, opens up new possibilities for the development of drugs that block MCRS1 to treat cancer and diabetes.

Under normal conditions, mTOR regulates essential cellular functions, such as protein synthesis and cell growth and proliferation. However, an overactive stimulation of mTOR in response to nutrients and growth factors −metabolic processes that are crucial in tumor biology− leads to an increase in cell growth and proliferation.

CORRELATION WITH PROGNOSIS IN COLORECTAL CANCER

CNIO researchers have now discovered how the MCRS1 protein –a protein associated with gene regulation and cell death processes− is capable of activating mTOR, and thus, stimulate cell proliferation. In this way, in human colorectal cancer samples, a correlation was found between increased MCRS1 activity and tumours with a high proliferation rate, as well as with a worse prognosis of the disease.

“Although in our study we published the results obtained from these colorectal samples, we are also studying the relationship between this protein and diseases of the liver, the primary metabolic organ,” explains Djouder.

ONE DISTINCTIVE FEATURE OF CANCER

The incidence of cancer and other related diseases has increased considerably in Western societies; this is partly due to an increased caloric intake and a more sedentary lifestyle. Therefore, unravelling the cellular processes that act in response to an excess of nutrients can contribute to achieve a better understanding of the biology of cancer and, consequently, is key to the fight against this disease.

“We will continue to study this gene using different genetically modified mouse models, where we can study what occurs when there is a gain- or loss-of-function. We are already obtaining interesting results, but further research is necessary.”

This research has been funded by the Spanish Ministry of Economy and Competitiveness (MINECO; SAF2010 - 18518) and the Spanish Ramón y Cajal Fellowship (MINECO).

Human colorectal cancer samples expressing low levels of MCRS1 low (left) and high levels of MCRS1 (right). / Nabil Djouder. CNIO

Reference article:

MCRS1 Binds and Couples Rheb to Amino Acid-Dependent mTORC1 Activation. Mohamad-­Ali Fawal, Marta Brandt, Nabil Djouder. Developmental Cell (2015). doi: 10.1016/j.devcel.2015.02.010

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