Completed Genetics & Molecular Biology Cancer

The E2F pathway: new levels of control and regulation

Funder MRC (part of UKRI)
Recipient organisation
Funding £1.8M
Period May 2011 — May 2016

In plain English

AI plain-English summary

A single protein called E2F acts as a master switch that tells cells when to start copying their DNA and divide—and in many cancers, that switch is stuck in the "on" position. This matters because cancer is fundamentally a disease of uncontrolled cell division. In healthy cells, the retinoblastoma protein (pRb) acts as a brake on E2F, preventing it from triggering DNA replication. But in most human tumours, pRb is disabled, leaving E2F permanently active and driving relentless cell growth. Researchers want to understand exactly how different forms of E2F activity are controlled, and how they contribute to both normal cell division and tumour growth. This is fundamental science with no immediate clinical application. However, because E2F is so central to the cell cycle and so frequently dysregulated in cancer, dissecting its control mechanisms could reveal new molecular targets for drugs. Past work on cell-cycle proteins has already produced therapies such as CDK inhibitors, now used to treat breast cancer. A deeper understanding of E2F regulation may similarly open routes to blocking tumour cell proliferation without harming healthy cells.

View original technical description
Cancer results from abnormal cell growth and division, and is frequently described as a disease of the cell cycle. The cell cycle refers to the process through which one cell grows and divides which, in normal healthy cells, is a tightly regulated process. The cell cycle is divided into four phases, where a major point of control exists as cells progress from the initial G1 phase into S phase, which is when cells begin to synthesise and copy their DNA in preparation for cell division. In mammalian cells, E2F is a control protein of central importance because it governs whether cells do or do not enter S phase. The activity of E2F is regulated by a number of key proteins that act as a ?braking? system, and includes the retinoblastoma tumour suppressor protein (pRb) which, by forming a protein complex with E2F, block E2F activity. Most importantly, in human tumour cells pRb is usually inactive, which means that the normally tightly regulated E2F activity is unleashed, providing a permanent signal that drives cells into unrestrained growth and division. The programme of study described here wants to dissect the role and regulation of different types of E2F activity, and assess the contribution to normal and tumour cell growth. Because of the abnormal control of E2F in cancer, this study is likely to identify new therapeutic opportunities for preventing the growth of tumour cells.

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Researchers

Nicholas La Thangue (Principal Investigator)

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Original classification

Research Grant

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