Signal transduction, cancer cell biology, metastasis, cell proliferation, differentiation, apoptosis.
signal transduction, tumor progression, Ras, Rap, cAMP.
Description of Research
Dr. Meinkoth's laboratory is interested in normal and aberrant growth regulation in thyroid follicular cells, specialized epithelial cells that synthesize, secrete and store thyroid hormone. Thyrotropin or TSH, the physiological regulator of thyroid cell proliferation, differentiation and survival, elicits many of its effects through the ubiquitous second messenger, cAMP. In addition to activating PKA, cAMP activates small G proteins, including Ras and Rap. The contributions of PKA, Ras and Rap1 to the regulation of cell proliferation, differentiation and survival are under investigation.
Ras mutations occur at high frequency in thyroid tumors where alterations in H-, K- and N-Ras have been identified. B-Raf mutations are also prevalent in thyroid tumors. Stable expression of oncogenic Ras in thyroid cells confers TSH-independent proliferation, induces dramatic morphological alterations and extinguishes differentiated gene expression. In contrast, acute expression of oncogenic Ras stimulates aberrant cell cycle progression and apoptosis. The molecular mechanism through which Ras deregulates cell cycle progression and stimulates apoptosis is under investigation. Identifying the secondary changes that transpire to allow the survival of cells expressing activated Ras is an area of active interest.
Expression of Rap1GAP, a negative regulator of Rap activity, is downregulated in many human tumors. The functional significance of Rap1GAP downregulation is unknown. Silencing the expression of Rap1GAP in human tumor cells enhanced cell spreading and impaired cell/cell adhesion. More recently, we showed that depletion of Rap1GAP endows cells with an altered mechanism of cell motility that is RAC1 dependent and that Rap1GAP-depleted cells exhibit increased invasive behavior. The contribution of Rap1GAP depletion to tumor progression is a major focus in the labortatory.
Dong X, Korch C, Meinkoth JL: Histone deacetylase inhibitors upregulate Rap1GAP and inhibit Rap activity in thyroid tumor cells. Endocr Relat Cancer 18(3): 301-310, 2011.
Tsygankova OM, Ma C, Tang W, Korch C, Feldman MD, Lv Y, Brose MS, Meinkoth JL: Downregulation of Rap1GAP in human tumor cells alters cell/matrix and cell/cell adhesion. Mol Cell Biol 30(13): 3262-3274, 2010.
Mei Y, Yong J, Liu H, Shi Y, Meinkoth J, Dreyfuss G, Yang X: tRNA binds to cytochrome c and inhibits caspase activation. Mol Cell 37(5): 668-678, 2010.
Vuchak LA, Tsygankova OM, Prendergast GV, Meinkoth JL: Protein kinase A and B-Raf mediate extracellular signal-regulated kinase activation by thyrotropin. Mol Pharmacol 76(5): 1123-1129, 2009.
Nellore A, Paziana K, Ma C, Tsygankova OM, Wang Y, Puttaswamy K, Iqbal AU, Franks SR, Lv Y, Troxel AB, Feldman MD, Meinkoth JL, Brose MS: Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab 94(3): 1026-1032, 2009.
Smirnova EV, Collingwood TS, Bisbal C, Tsygankova OM, Bogush M, Meinkoth JL, Henderson EE, Annan RS, Tsygankov AY: TULA proteins bind to ABCE-1, a host factor of HIV-1 assembly, and inhibit HIV-1 biogenesis in a UBA-dependent fashion. Virology 372: 10-23, 2008.
Tsygankova OM, Prendergast GV, Puttaswamy K, Wang Yan, Feldman MD, Wang H, Brose MS, Meinkoth JL: Downregulation of Rap1GAP contributes to Ras transformation. Mol Cell Biol 27: 6647-6658, 2007.
Dworet JH and Meinkoth JL: Interference with 3',5'-cyclic adenosine monophosphate response element binding protein stimulates apoptosis through aberrant cell cycle progression and checkpoint activation. Molec Endocrinol 20: 1112-1120, 2006.
Fikaris AJ, Lewis AE, Abulaiti A, Tsygankova OM, Meinkoth JL: Ras triggers ataxia-telangiectasia-mutated and Rad-3-related activation and apoptosis through sustained mitogenic signaling. J Biol Chem 281: 34759-34767, 2006.
Abulaiti A, Fikaris AJ, Tsygankova OM, Meinkoth JL: Ras induces chromosome instability and abrogation of the DNA damage response. Cancer Res 66(21): 10505-10512, 2006.
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Last updated: 08/06/2012
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