- TSC2 Regulates Cell Motility and Invasiveness
- TSC1 and TSC2 Regulate Neuronal Morphology and Function
- Tuberin Regulates mTOR Function in Response to Hypoxia
TSC2 Regulates Cell Motility and Invasiveness
Posted June 22, 2006
Vera P. Krymskaya, Ph.D., University of Pennsylvania, Philadelphia, PennsylvaniaTuberous sclerosis complex (TSC) is a genetic disorder arising from inactivating mutations in the tumor suppressor genes TSC1 or TSC2. The complex formed by TSC1 and TSC2 proteins has long been associated with the regulation of protein synthesis and cell growth, achieved through inhibition of the mammalian target of rapamycin (mTOR) signaling pathway. However, neurologic complications of TSC, such as epilepsy, autism, and cognitive impairments, are considered to result from perturbations in neuronal migration. Similarly, lymphangioleiomyomatosis (LAM), a progressive lung disease that is another common complication of TSC, is also associated with loss of TSC1 and TSC2 function due to cell migration and metastasis. Dr. Vera P. Krymskaya of the University of Pennsylvania therefore hypothesized that complex formation between TSC1 and TSC2 regulates cell adhesion and motility and that dysregulation of the complex formation may contribute to the pathogenesis of TSC. With funding from a Department of Defense Tuberous Sclerosis Complex Research Program Fiscal Year 2003 Idea Development Award, Dr. Krymskaya and her colleagues found that TSC2 plays a critical role in regulating actin cytoskeleton, focal adhesion, cell motility, and invasiveness. TSC2 is required for Rac1 activation. Binding of TSC2 to TSC1 inhibits the Rho-activating function of TSC1, preventing abnormal cell migration and invasiveness. When TSC2 is mutated, as seen in the disease state, TSC1 inhibits Rac1, activates Rho, and promotes cell migration and invasiveness. These results indicate that loss of function of TSC2 results in downregulation of Rac1 and upregulation of Rho activities, leading to abnormal cell motility and invasiveness associated with the pathology of both TSC and LAM.
Publications:
Goncharova E, Goncharov D, Noonan D, and Krymskaya VP. 2004. TSC2 modulates actin cytoskeleton and focal adhesion through TSC1-binding domain and the Rac1 GTPase. The Journal of Cell Biology 167(6):1171-1182.
Goncharova EA, Goncharov DA, Lim PN, Noonan D, and Krymskaya VP. 2006. Modulation of cell migration and invasiveness by tumor suppressor TSC2 in lymphangioleiomyomatosis. American Journal of Respiratory Cell and Molecular Biology 34:473-480.
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Abstract: The Role of TSC Proteins in Regulating Cell Adhesion and Motility
TSC1 and TSC2 Regulate Neuronal Morphology and Function
Posted April 26, 2006
Bernardo Sabatini, Ph.D., Harvard Medical School, Boston, MassachusettsTuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in the TSC1 (hamartin) or TSC2 (tuberin) tumor suppressor genes. Many children with TSC have neurological symptoms including epilepsy, mental retardation, and autism. However, the molecular mechanisms underlying these neuropathologies are unclear. Therefore, understanding the neural functions of TSC1 and TSC2 could lead to improved treatments for neurological disorders in TSC patients. Dr. Bernardo Sabatini of Harvard Medical School hypothesized that TSC1 is necessary in mature, differentiated neurons for the establishment of proper neuronal morphology and synaptic function. He believes that disruption of TSC1 results in the function of each neuron being perturbed and that, because of these defects in each brain cell, the brain as a whole does not function properly. This is in contrast to the conventional hypothesis that the presence of tumors within the brain creates a disorganized brain architecture. With funding from a Department of Defense Tuberous Sclerosis Complex Research Program Fiscal Year 2003 Idea Development Award, Dr. Sabatini and his research team examined the role of the TSC pathway in regulating the growth of post-mitotic differentiated neurons in a cell-autonomous manner. By downregulating the levels of TSC1 and TSC2 in cell culture and animal models, the research team showed that the TSC pathway regulated soma size, the density and size of dendritic spines, and the properties of excitatory synapses in hippocampal pyramidal neurons. Loss of a single copy of TSC1, as is observed in the neurons of TSC patients, was sufficient to disrupt dendritic spine structure. Interestingly, these morphological effects were independent of regulation of TSC2 by Akt, but they did require rapamycin-sensitive mTOR activity and regulation of cofilin (an actin depolymerization factor). These results indicate that the TSC pathway regulates neuronal structure and function and that cell-autonomous disruptions of synapse function contribute to neurological symptoms of TSC.
Publications:
Tavazoie SF, Alvarez VA, Ridenour DA, Kwiatkowski DJ, and Sabatini BL. 2005. Nature Neuroscience 8(12):1727-1734.
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Abstract: The Role of TSC1 in the Formation and Maintenance of Excitatory Synapses
Tuberin Regulates mTOR Function in Response to Hypoxia
Posted April 3, 2006
William Kaelin, Jr., M.D., Dana-Farber Cancer Institute, Boston, MassachusettsTuberous sclerosis complex is caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin) tumor suppressor genes. The disorder is associated with increased activity of mammalian target of rapamycin (mTOR), a central regulator of protein synthesis and cell growth that is inhibited by chronic oxygen deprivation (hypoxia). Tumor hypoxia has been associated with a negative prognosis in several types of cancers. With funding from a Department of Defense Tuberous Sclerosis Complex Research Program Fiscal Year 2003 Idea Development Award, Dr. William Kaelin of the Dana-Farber Cancer Institute has discovered that the TSC1/TSC2 protein complex regulates mTOR in response to hypoxia. Dr. Kaelin and his research team showed that an intact TSC1/TSC2 complex is required for mTOR inhibition by hypoxia. Inactivation of TSC2 conferred a proliferative advantage to cells grown under hypoxic conditions. Dr. Kaelin's group further defined the mechanisms of TSC1/TSC2-mediated mTOR inhibition under hypoxic conditions. Downregulation of mTOR by hypoxia requires expression of the hypoxia-inducible Redd1 gene but is independent of the AMP-activated protein kinase (AMPK) and Peutz-Jehgers syndrome (Lkb1) genes, which are involved in TSC1/TSC2-mediated mTOR inhibition under conditions of energy depletion. The investigators also found that TSC2 is required for Redd1 to downregulate phosphorylation of S6K, an mTOR substrate; these data indicate that Redd1 may act upstream of TSC1/TSC2 to downregulate mTOR in response to hypoxia. Improved understanding of the role of TSC2 in response to hypoxia may lead to better treatments for tumors associated with tuberous sclerosis complex.
Publications:
Brugarolas J, Lei K, Hurley RL, Manning BD, Reiling JH, Hafen E, Witters LA, Ellisen LW, and Kaelin WG Jr. 2004. Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex. Genes and Development 18(23):2893-2904
Brugarolas J. and Kaelin WG Jr. 2004. Dysregulation of HIF and VEGF is a unifying feature of the familial hamartoma syndromes. Cancer Cell 6(1):7-10.
Brugarolas JB, Vazquez F, Reddy A, Sellers WR, Kaelin WG Jr. 2003. TSC2 regulates VEGF through mTOR-dependent and -independent pathways. Cancer Cell 4(2):147-158.
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Abstract: Hypoxia-Inducible Factor Regulation by the TSC2 Tumor Suppressor Protein