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Jul 10, 2014

Master Switch Boosts Productivity, Expands Capacity of Cellular Factories

  • In a factory, excess inventory is usually taken as a signal to slow production, unless demand is surging. In that case, the factory might expand its capacity. To deal with such contingencies, the factory presumably relies on good management. Similarly, the cell’s protein factory, the endoplasmic reticulum (ER), has means of responding to signals. However, when cellular management is deranged, as in cancer, the ER may sustain elevated metabolic rates and support runaway growth.

    Unlike healthy cells, cancer cells are constantly growing, and so need to keep making proteins and lipids. In healthy cells, constant growth can overwhelm cellular factories like the ER, leading to cell stress and death, but cancer cells manage to keep their factories running at high capacity.

    To explore how ER function is maintained during changes in cell behavior and environmental fluctuations, scientists at The Institute of Cancer Research (ICR) performed a systems-level analysis of ER homeostasis. In so doing, they managed to identify a molecular trigger responsible for ratcheting up activity of the ER.

    A protein in the TOR (target of rapamycin) signaling pathway, called SREBP (sterol regulatory element binding protein), appears to allow cancer cells to produce enough proteins and lipids to fuel their non-stop growth. In addition, SREBP controls the flow of messages to the ER, telling it to expand.

    These findings, which may help uncover future targets for cancer treatment, appeared July 9 in PLOS ONE, in an article entitled, “Signaling Networks Converge on TORC1-SREBP Activity to Promote Endoplasmic Reticulum Homeostasis.”

    The article describes how the ICR researchers found that while signaling networks that regulate ER function have a largely modular architecture, the TORC1-SREBP signaling axis is a central node that integrates signals emanating from different subnetworks. “TORC1-SREBP promotes ER homeostasis by regulating phospholipid biosynthesis and driving changes in ER morphology,” the authors wrote. “In particular, our network model shows TORC1-SREBP serves to integrate signals promoting growth and G1-S progression in order to maintain ER function during cell proliferation.”

    The scientists also report how they used the cells of fruit flies, modified with a fluorescent marker that is activated when the cells are put under stress, to identify the signals responsible for driving up activity of the ER. They systematically silenced genes thought to be important to the smooth working of the ER and measured the stress signals produced in response.

    They found that silencing the TOR signaling pathway—activated in many different types of cancer—increased ER stress in the cells. When they blocked TOR signals, cells took longer to recover from ER stress and the ER factory shrank.

    These findings suggest the TOR signaling pathway promotes cell growth while simultaneously ensuring productivity of the ER matches this growth. And the protein SREBP, which is part of the TOR signaling pathway, appeared to be essential for promoting expansion of the ER, and ensuring it carried out its factory activities effectively.

    “We have discovered the key role played by the TOR signaling pathway in driving the expansion of the endoplasmic reticulum, and sending a cell’s factories into overdrive,” said Chris Bakal, Ph.D., leader of ICR’s Dynamical Cell Systems Team. “The TOR pathway is active in many types of cancer, and our study provides new insights into how cancer metabolism works, and suggests that these metabolic signals could be excellent targets for future treatments.”


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