Our laboratory studies the role of the PI3K/AKT/mTOR signaling pathway in the pathogenesis of Tuberous Sclerosis Complex (TSC), sporadic pulmonary Lymphangioleiomyomatosis (LAM), and cancer. TSC and LAM are caused by mutations in the TSC1 and TSC2 tumor suppressor genes and exhibit aberrant AKT/mTOR signaling. The protein products of TSC1 and TSC2, termed hamartin and tuberin respectively, form a functional heterodimer that inhibits the rapamycin-sensitive mTOR/raptor complex (mTORC1), a central kinase regulating translation, ribosome biogenesis, cell cycle, angiogenesis, autophagy, and apoptosis. Additionally, the hamartin/tuberin complex is a positive regulator of the rapamycin-insensitive mTOR/rictor complex (mTORC2), which is involved in actin cytoskeleton functions. In response to various stimuli, hamartin and tuberin are phosphorylated by multiple kinases. Currently, all treatment regimens for TSC and LAM are symptomatic. The identification of mTORC1 as a downstream target of the hamartin/tuberin complex led to the hypothesis that rapamycin can be used for the treatment of TSC and LAM. Clinical trials are ongoing.
We found that during mitosis hamartin is phosphorylated by CDK1(cdc2)/cyclin B, and interacts with the mitotic kinase PLK1. Additionally, hamartin-null cells have multiple centrosomes and increased DNA content. Our current work focuses on the role of the hamartin-PLK1 interaction in the pathogenesis of TSC and LAM. More specifically, we investigate how the interaction between hamartin and PLK1 regulates the mTOR pathway, and how hamartin, tuberin, and other mTOR pathway components regulate centrosome duplication, mitotic progression, and genomic stability. Additionally, we evaluate the therapeutic potential of PLK1 inhibitors in cell culture models for TSC and LAM.
The PI3K/mTOR pathway interacts with and integrates signals from a variety of other pathways to control cell growth. A second area of interest in our research is the identification of novel drugable targets interacting with the PI3K/mTOR pathway and the identification of drugs that can preferentially inhibit the growth and induce apoptosis of hamartin- and tuberin-null cells. We recently initiated a cell-based screen of FDA-approved oncology drugs. Top candidates are being validated in additional assays. Ultimately, these drugs will be tested in preclinical animal models for TSC and LAM for their ability to inhibit tumor development.
Our research is funded by the Department of Defense, and the Tuberous Sclerosis Alliance.
More information: Lab webpage
Selected Publications.
Gómez-Baldó, L. et al., TACC3-TSC2 maintains nuclear envelope structure and controls cell division. Cell Cycle 9 (6), 1143 (2010). PMID: 20237422
Astrinidis, A. et al. The transcription factor SP1 regulates centriole function and chromosomal stability through a functional interaction with the mammalian target of rapamycin/raptor complex. Genes Chromosomes Cancer. 49 (3), 282 (2010). PMID: 20013896
Matthew, E.M., et al., The p53 target Plk2 interacts with TSC proteins impacting mTOR signaling, tumor growth and chemosensitivity under hypoxic conditions. Cell Cycle 8 (24), 4168 (2009). PMID: 20054236
Yu, J.J., et al., Estrogen promotes the survival and pulmonary metastasis of tuberin-null cells. Proc. Natl. Acad. Sci. USA 106 (8), 2635 (2009). PMID: 19202070
Astrinidis, A., et al., Hamartin, the tuberous sclerosis complex 1 gene product, interacts with polo-like kinase 1 in a phosphorylation-dependent manner. Hum. Mol. Genet. 15 (2), 287 (2006). PMID: 16339216
Astrinidis, A. and Henske, E. P., Tuberous sclerosis complex: linking growth and energy signaling pathways with human disease. Oncogene 24 (50), 7475 (2005). PMID: 16288294
Astrinidis, A., et al., Cell cycle-regulated phosphorylation of hamartin, the product of the tuberous sclerosis complex 1 gene, by cyclin-dependent kinase 1/cyclin B. J. Biol. Chem. 278 (51), 51372 (2003). PMID: 14551205
Astrinidis, A. et al., Tuberin, the tuberous sclerosis complex 2 tumor suppressor gene product, regulates Rho activation, cell adhesion and migration. Oncogene 21 (55), 8470 (2002). PMID: 12466966
Carsillo, T., et al., Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc. Natl. Acad. Sci. U. S. A. 97 (11), 6085 (2000). PMID: 10823953 |