Signal Pathway On Mitochondria Decides Whether The Cell Lives Or Dies

Main Category: Biology / Biochemistry
Also Included In: Cancer / Oncology
Article Date: 16 Oct 2007 - 7:00 PDT

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ETH Zurich researchers discovered on the mitochondria, the cell's power stations, a signal pathway that decides whether the cell lives or dies. The same signal path also occurs in other cell compartments.

Professor Wilhelm Krek and his post-doc Nabil Djouder from ETH Zurich's Institut for Cell Biology are excited. For five years Djouder has worked on a new signal pathway in animal cells. The pair have now submitted a scientific publication described by Krek as the basis for many more "extremely interesting research projects in cancer or diabetes research". The paper is published in the scientific journal "Molecular Cell".

Researchers already knew that cells commit suicide if insufficient nutrients such as amino-acids and growth factors or hormones are available to them. Mitochondria, the cell's power stations, are responsible for triggering cell death. Djouder and Krek have now located the molecules and described in detail the processes that control a cell's growth, survival and even its death. Krek stresses that "A cell's growth and death are co-ordinated via the same signal network."

Almost as a by-product of their work they discovered that the signal pathway can occur not just once at a particular point in the cell. The components of the signalling network are also present in the cytoplasm (cytosol), and operate independently of those attached to the mitochondria.

Maintain the equilibrium

The ETH Zurich researchers demonstrate that the new signal pathway contains several components situated on the outer envelope of the mitochondria. If insufficient hormones or nutrient constituents are available to the cell, the susceptibility increases and the cell dies, but not just yet.

Hormones or amino-acids reaching the cell trigger a cascade of various signals via a molecule called mTOR (mammalian Target of Rapamycin). mTOR passes on the message about the arrival of nutrients to the kinase S6K1, which is a protein. The latter stimulates cell growth and suppresses the cell death factor BAD. Simultaneously, however, S6K1 also cleaves a molecule complex on the envelope of the mitochondria. One of the components (PP1gamma) is liberated and begins to suppress the activity of the kinase S6K1, i.e. it is its opposite number. This seems to protect the cell against "death resistance". The researchers also have evidence that PP1gamma reactivates the cell death initiator BAD which the S6K1 had deactivated. The cell's aim is to maintain its internal equilibrium and also to be able to die if necessary.

New approach in cancer therapy

However, Krek and Djouder are already one step ahead. Djouder says "We would like to intervene purposefully in this fundamental mechanism, for example to send cancer cells to their death." The new discoveries possibly open up new avenues of approach in cancer therapy. This is because the researchers have recognised that a cell's growth and death are closely interlinked. The idea is to employ a combination therapy of different active ingredients to stop cancer cells' incessant urge to grow and to send the degenerate cells to their death. This is done nowadays with various types of cancer by using the active ingredient Rapamycin which blocks the trigger substance mTOR, informing the cell that no nutrients are available for growth. That ultimately sends the cell to its death.

A previous publication by Krek's laboratory describing the factors in the cell death signalling network in the scientific journal 'Science' was the starting point for the present paper. The ETH Zurich researchers have now investigated this discovery further and have elucidated the function of the signalling network that is controlled by mitochondria. Wilhelm Krek stresses that this was possible only by using all possible techniques and methods and through interdisciplinary collaboration with other research groups. Imaging is central

Another of the research group's aims is to find out how the signalling networks are co-ordinated with one another. For example the researchers want to measure the activity of the various signal pathways to discover where and when which path is followed. Krek and Djouder would like to achieve this by using fluorescent marker substances which they can follow in the cell in real time. Krek says "Imaging is central to systems biology and has a gigantic future potential."

Reference:

* Djouder et al., S6K1-Mediated Disassembly of Mitochondrial URI/PP1g Complexes Activates a Negative Feedback Program that Counters S6K1 Survival Signaling, Molecular Cell (2007), doi:10.1016/j.molcel.2007.08.010

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