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HSCI Science Update: March 2009

March 2, 2009

  • Understanding the "Smoothened" Receptor in the Hedgehog Signaling Pathway

    The signaling pathway called "hedgehog" plays a critical role not only in embryonic development and body patterning but also functions in the adult. Numerous diseases such as basal cell carcinoma have been linked to defects in this pathway. Sonic hedgehog, a mammalian version of hedgehog protein, has been shown to stimulate the proliferation of several types of adult stem cells. A key component of the hedgehog signaling pathway is "Smoothened" (SMO), a receptor in the cell membrane that can receive signals at the cell surface and transduce them to downstream pathway components. Therefore, SMO is the therapeutic target of many drugs designed to treat hedgehog pathway-related diseases including many types of cancers and limb formation abnormalities such as Brachydactyly, as it is essential for transmission of the signal across the cell membrane. Thus, a better mechanistic understanding of how SMO translocates across the membrane to relay its signal and how it interacts with drugs is therapeutically valuable. A recently published paper by HSCI Principal Faculty Andy McMahon and colleagues at the Harvard Stem Cell Institute describes how they created a system in which they were able to label all SMO in the cell membrane with a fluorescent tag. They used this system to explore the mechanism of action of two hedgehog pathway antagonist drugs and showed that most of the SMO in the cell membrane traffics to the cilia, hair-like projections in the cell, in response to a pathway agonist. This increased understanding of the hedgehog pathway that is involved in adult stem cell proliferation and creation of this system which can observe a drug's mode of action has exciting potential implications for controlling the proliferation of adult stem cells, including potentially cancer stem cells. Inappropriate activation of the hedgehog pathway may be linked with the transformation of adult stem cells to cancer stem cells and hedgehog pathway antagonists could have tremendous potential to inhibit this transformation. Studies like the one by MacMahon and his fellow researchers, which give us a clearer glimpse at the therapeutic modality of potential drugs, will be increasingly valuable as we work to develop treatments.

    Wang, Y., Zhou, Z., Walsh, C.T., McMahon, A.P. (2009). Selective translocation of intracellular Smoothened to the primary cilium in response to Hedgehog pathway modulation. Proc Natl Acad Sci USA. Feb 5. [Epub ahead of print]

  • Heart Disease and Calcium Signaling

    Cardiac hypertrophy is a thickening of the heart muscle due to an increase in size of heart muscle cells, or cardiomyocytes. It is commonly caused by high blood pressure and causes a reduction in the size of the heart chambers and is associated with heart failure. Changes in cardiomyocyte appearance and function are correlated with changes in gene expression. One key signaling pathway active in cardiomyocytes is the calcium signaling pathway. Calcium, and its cognate binding protein calmodulin, can activate a cascade of genes leading to cardiac hypertrophy, therefore, proper control of calcium signaling in cardiomyocytes is critical. In an effort to better understand how calmodulin levels are regulated in heart failure, HSCI Principal Faculty William Pu and colleagues recently found that a microRNA, a short stretch of nucleic acids that regulate gene expression, called miR-1 is downregulated in a mouse model of heart failure. They found that miR-1 is important for regulating calcium-dependent signaling levels and its reduced expression causes consequently higher levels of calcium and associated cardiac hypertrophy. These results have important implications for our understanding of how the calcium signaling pathways involved in cardiac hypertrophy are regulated and also enhance our understanding of cardiomyocyte gene expression and its consequences for heart development and function.

    Ikeda S, He A, Kong SW, Lu J, Bejar R, Bodyak N, Lee KH, Ma Q, Kang PM, Golub TR, Pu WT. (2009). microRNA-1 negatively regulates expression of the hypertrophy-associated genes calmodulin and Mef2a. Mol Cell Biol. Feb 2. [Epub ahead of print]