Immune-mediated cell destruction is one of the central pathologic events in the development of autoimmune disease. In Hashimoto's thyroiditis (HT), a specific immune response to thyroid antigens leads to lymphocytic infiltration, follicular cell destruction and clinical hypothyroidism. It is now evident that apoptosis is one of the major pathologic mechanisms underlying HT and other forms of autoimmune disease. Proinflammatory cytokines are thought to play an initiating role in autoimmunity and apoptosis. Interferon-gamma (IFN-gamma) and interleukin 1-beta have been implicated in the pathogenesis of HT and other autoimmune disorders. Recently, these cytokines were shown to induce Fas receptor expression on normal human thyrocytes, cells that express FasL. Cross-linking of Fas resulted in massive apoptosis, leading to the speculation that following inflammation and cytokine release, thyroid cells are pruned to die by fratricidal mechanisms. Thyrotropin (TSH) regulates thyroid function, proliferation and possibly, survival. TSH stimulates the expression of thyroid-specific genes, effects that are opposed by (IFN-gamma). In turn, TSH has been reported to decrease IFN-gamma effects on Fas expression and apoptosis.
Our aims are to elucidate the effects of proinflammatory cytokines in a continuous line of rat thyroid cells. We wish to explore the mechanisms of cytokine-induced cell death, and of survival promoted by TSH using a combination of biochemistry, cell biology and microinjection. Crosstalk between cytokines and hormones, given their opposing effects on Fas expression, may significantly alter the susceptibility of endocrine cells to apoptosis, a factor with profound implications for autoimmune diseases including thyroiditis, diabetes and rheumatoid arthritis. Ras activation, a frequent event in thyroid cancer, sensitizes many cells to cytokine-induced apoptosis, and numerous studies implicate a close linkage between signals activated by Ras and Fas. TSH appears to alter the balance in Ras-mediated signals from proliferation to apoptosis, a finding that may explain the infrequent occurrence of mutations in Ras and in Gs or the TSH receptor, mutations leading to the constitutive activity cAMP- mediated signaling pathways, in thyroid tumors. We will examine the acute effects of Ras on apoptosis, and the signaling pathways responsible for these effects. We will identify cellular factors that contribute to the ability of Ras-transformed cells to escape apoptosis. Taken together, these studies will provide new insight into the regulation of thyroid cell survival and transformation applicable to other endocrine cells.
| Nellore, Anoma; Paziana, Karolina; Ma, Changqing et al. (2009) Loss of Rap1GAP in papillary thyroid cancer. J Clin Endocrinol Metab 94:1026-32 |
| Vuchak, Lisa A; Tsygankova, Oxana M; Prendergast, Gregory V et al. (2009) Protein kinase A and B-Raf mediate extracellular signal-regulated kinase activation by thyrotropin. Mol Pharmacol 76:1123-9 |
| Tsygankova, Oxana M; Prendergast, Gregory V; Puttaswamy, Kanchan et al. (2007) Downregulation of Rap1GAP contributes to Ras transformation. Mol Cell Biol 27:6647-58 |
| Fikaris, Aphrothiti J; Lewis, Aurelia E; Abulaiti, Adili et al. (2006) Ras triggers ataxia-telangiectasia-mutated and Rad-3-related activation and apoptosis through sustained mitogenic signaling. J Biol Chem 281:34759-67 |
| Dworet, Jessica H; Meinkoth, Judy L (2006) Interference with 3',5'-cyclic adenosine monophosphate response element binding protein stimulates apoptosis through aberrant cell cycle progression and checkpoint activation. Mol Endocrinol 20:1112-20 |
| Abulaiti, Adili; Fikaris, Aphrothiti J; Tsygankova, Oxana M et al. (2006) Ras induces chromosome instability and abrogation of the DNA damage response. Cancer Res 66:10505-12 |
| Cheng, Guanjun; Lewis, Aurelia E; Meinkoth, Judy L (2003) Ras stimulates aberrant cell cycle progression and apoptosis in rat thyroid cells. Mol Endocrinol 17:450-9 |
| Saavedra, Arturo P; Tsygankova, Oxana M; Prendergast, Gregory V et al. (2002) Role of cAMP, PKA and Rap1A in thyroid follicular cell survival. Oncogene 21:778-88 |
| Cheng, G; Meinkoth, J L (2001) Enhanced sensitivity to apoptosis in Ras-transformed thyroid cells. Oncogene 20:7334-41 |
