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Riding the Waves: How Our Cells Send Signals

Within seconds, NF-<sub>κ</sub>B quickly scans the genome in the nucleus, searching for the appropriate targets to activate. Within minutes, NF-<sub>κ</sub>B shuttles between the nucleus and cytoplasm to detect cell signals and to potentially refresh its activation following exposure to inactivating signals.
Within seconds, NF-κB quickly scans the genome in the nucleus, searching for the appropriate targets to activate. Within minutes, NF-κB shuttles between the nucleus and cytoplasm to detect cell signals and to potentially refresh its activation following exposure to inactivating signals.

The ability of cells to perceive and respond to their environment is critical in order to maintain basic cellular functions such as development, tissue repair, and response to stress. This process happens through a complex system of communication, called cell signaling, which governs basic cellular activities and coordinates cell actions. Errors in cell signaling have been linked to numerous diseases, including cancer. NF-κB is a protein complex that plays a critical role in many cell signaling pathways by controlling gene activation. It is widely used by cells to regulate cell growth and survival and helps to protect the cell from conditions that would otherwise cause it to die. Many tumor cells have mutations in genes that cause NF-κB to become overactive. Blocking NF-κB could cause tumor cells to stop growing, die, or become more sensitive to therapeutics.

Myong-Hee Sung, Ph.D., a staff scientist in the Laboratory of Receptor Biology and Gene Expression at the CCR, is working to gain a better understanding of NF-κB signaling. Dr. Sung favors a systems biology approach, which utilizes mathematical modeling and fluorescence imaging in single live cells. Her strategy has an advantage over traditional biochemical methods, which can only report signals from large populations of cells and thus miss important dynamic patterns that exist in single cells. A recent paper published by Dr. Sung and her colleagues in PLoS ONE revealed that NF-κB activity is extremely dynamic and occurs in distinct waves, or oscillations. NF-κB activity is controlled in part by its movement from the cytoplasm, or main body of the cell, to the nucleus, or control center of the cell, where genes reside. Previous studies suggest that after activation, NF-κB is rapidly inactivated through negative feedback signals and moves from the nucleus back to the cytoplasm. However, Dr. Sung has shown that oscillations in NF-κB activity are sustained and continue to ride along genes in search of targets long after the initial activating signal has faded.

Using cells that express a fluorescently labeled component of NF-κB, Dr. Sung has been able to visualize NF-κB activation and its movement from the cytoplasm to the nucleus. She found that different characteristics of NF-κB signaling dynamics could be observed in disparate timescales from seconds to hours. Within seconds, NF-κB quickly scans the genome in the nucleus, searching for the appropriate targets to activate. Within minutes, NF-κB shuttles between the nucleus and cytoplasm to allow a sampling of cell signals and to potentially refresh its activation following exposure to inactivating signals. These finer-scale dynamics are superimposed and interlinked with oscillations in the amount of NF-κB in the nucleus that are sustained over hours and are determined by distinct negative feedback loops. Computer simulations of a mathematical model suggest that cells have fine-tuned the negative feedback loops to achieve oscillatory waves of NF-κB activity. Dr. Sung proposes that the negative feedback loops do not simply terminate NF-κB signaling but, instead, promote oscillations of NF κB in the nucleus.

Understanding signaling pathways at the single-cell level can greatly enhance our knowledge of tumor growth and drug resistance. This insight will contribute to the selection of appropriate targets for drug therapy and help to minimize drug toxicity and maximize efficacy.

Reference
PLoS ONE. 2009 Sep 29;4(9):e7163. PubMed link

Reviewed by Donna Kerrigan