Cellular stress activates an important anti-cancer protein

Researchers at UPF have discovered that the RB protein, responsible for stopping cell proliferation and therefore preventing tumour formation, is activated under cellular stress. The work, led by Eulàlia de Nadal and Francesc Posas, leaders of the research group on Cell Signalling of the Department of Experimental and Health Sciences in collaboration with the groups of Baldo Oliva (UPF) and Francisco X. Real (UPF/CNIO), is published in the journal Molecular Cell.

RB (Retinoblastoma) is a tumour suppressor protein that is altered in many cancers such as lung cancer, melanoma, prostate cancer or breast cancer. Originally, this alteration was detected in retinal cancer, hence its name. One of the main functions of RB is to inhibit cell cycle progression before genome duplication, so that cell does not divide until the right conditions are met. Therefore, RB prevents cell proliferation under physiological conditions. Thus RB inactivation may involve the development of cancer, since uncontrolled cellular proliferation results in tumour formation.

The work done by scientists at the Cell Signalling research group has found that RB is also important to stop cell progression in response to cellular stress. Under these conditions, the brake is essential for cell survival. A highly remarkable fact is that this new mechanism predominates over others that normally regulate the activity of RB. Therefore, the external activation of this mechanism could be used to block cell division.

As Francesc Posas, co-leader of the study says, “this discovery may be relevant in cancer biology because RB is a key protein in cell proliferation and many types of tumour coincide on the inactivation of this protein. If we get to reverse this inhibition, we could stop proliferation”.

In fact, an RB mutated protein that mimics the activating effect of RB is able to stop cell proliferation in cancer cells. “To carry out our study, we expressed a mutant form of RB that behaves like a super-repressor that blocks the proliferative activity of the cells. Now the challenge is to express this super-repressor in malignant cells in order to unalter the other cells of the body”, says Eulàlia de Nadal, co-leader of the article.

With this discovery, the RB protein is reconsidered as a target for drug discovery. Those molecules that are able to mimic its regulation could be of great interest to block cancerous cell proliferation processes and could therefore be used as potential therapeutic agents. One of the most interesting aspects of this discovery is the potential of RB as a target for the treatment of various cancers. “Initial studies in cells from different cancers seem to indicate that most of them can block their proliferation through this mechanism”, the authors say.

This work represents a significant advance in the field of biology and was conducted by the research group in Cell Signalling at the Department of Experimental and Health Sciences at UPF (DCEXS), led by the researchers Francesc Posas and Eulàlia de Nadal in collaboration with groups led by Baldo Oliva (UPF) and Francisco X. Real (UPF / CNIO).

Figure 1: Visual summary of the investigation. RB is phosphorylated and inactivated by CDK. Gubern et al. demonstrate that phosphorylation of the N-terminal end carried by RB in response to stress restricts p38 transcriptional activity of E2F, improving cell survival. This phosphorylation or the mutations that mimic it make RB avoid the inactivation of CDK and become capable of blocking the proliferation of cancer cells.

Figure 2: Activation of RB inhibits proliferation in cultured breast cancer cells.

Figure 3: Activation of RB under cellular stress.

Reference work: Gubern A, Joaquin M, Marquès M, Maseres P, Garcia-Garcia J, Amat R, González-Nuñez D, Oliva B, Real FX, de Nadal E and Posas F. The N-terminal phosphorylation of RB by p38 bypasses its inactivation by CDKs and prevents proliferation in cancer cells. Molecular Cell. (2016).