Ca2+ plays an important role in the liver. In the cytosol, it regulates activities such as bile secretion, glucose metabolism and cytoskeletal organization. We hypothesize that Ca2+ in the neoplasm instead regulates processes such as hepatic growth and regeneration and gene transcription. The mechanism by which nucleoplasmic Ca2+ is regulated thus is of great potential importance. It has been suggested that nuclear Ca2+ passively follows cytosolic Ca2+, but our preliminary data instead suggest that there is nuclear machinery that allows nucleoplasmic Ca2+ to be controlled independent of the Ca2+ concentration in the cytosol. Such machinery would in turn allow independent regulation of Ca2+- mediated events in the nucleus. Since the inositol 1,4,5,-triphosphate (InsP3) receptor regulates Ca2+ signaling in hepatocytes, our hypothesis will be tested by systematically defining the mechanisms and effects of nuclear Ca2+ signaling in liver through the following projects: Project A The organization of nuclear Ca2+ stores and the factors that regulate release of Ca2+ from these stores will be determined in intact hepatocytes and in liver cell lines. Project B The function and regulation of both native and cloned nuclear InsP3 receptors of hepatocytes will be characterized at the single channel level. Project C The role of the mitogen-activated protein kinase (MAPK) phosphatase-1 (MAPK-1) in controlling MAPK-mediated liver-specific gene transcription events in response to nuclear Ca2+ signals will be examined. Project D The significance of nuclear Ca2+ signals for gene transcription in liver will be examined by determining how genes integral to liver- specific functions are regulated by Ca2+ and by Ca2+-mobilizing bile acids. To help carry out these projects, core facilities will be established for cell and molecular biology, cell imaging, and administration.
| Qian, Kevin; Wang, Simeng; Fu, Minnie et al. (2018) Transcriptional regulation of O-GlcNAc homeostasis is disrupted in pancreatic cancer. J Biol Chem 293:13989-14000 |
| Boeckel, Göran R; Ehrlich, Barbara E (2018) NCS-1 is a regulator of calcium signaling in health and disease. Biochim Biophys Acta Mol Cell Res : |
| Lawan, Ahmed; Min, Kisuk; Zhang, Lei et al. (2018) Skeletal Muscle-Specific Deletion of MKP-1 Reveals a p38 MAPK/JNK/Akt Signaling Node That Regulates Obesity-Induced Insulin Resistance. Diabetes 67:624-635 |
| Franca, Andressa; Filho, Antonio Carlos Melo Lima; Guerra, Mateus T et al. (2018) Effects of endotoxin on type 3 inositol 1,4,5-trisphosphate receptor in human cholangiocytes. Hepatology : |
| Lemos, Fernanda O; Ehrlich, Barbara E (2018) Polycystin and calcium signaling in cell death and survival. Cell Calcium 69:37-45 |
| Giehl, Esther; Lemos, Fernanda O; Huang, Yan et al. (2017) Polycystin 2-dependent cardio-protective mechanisms revealed by cardiac stress. Pflugers Arch 469:1507-1517 |
| Feriod, Colleen N; Oliveira, Andre Gustavo; Guerra, Mateus T et al. (2017) Hepatic Inositol 1,4,5 Trisphosphate Receptor Type 1 Mediates Fatty Liver. Hepatol Commun 1:23-35 |
| Kruglov, Emma; Ananthanarayanan, Meenakshisundaram; Sousa, Pedro et al. (2017) Type 2 inositol trisphosphate receptor gene expression in hepatocytes is regulated by cyclic AMP. Biochem Biophys Res Commun 486:659-664 |
| Lawan, Ahmed; Bennett, Anton M (2017) Mitogen-Activated Protein Kinase Regulation in Hepatic Metabolism. Trends Endocrinol Metab 28:868-878 |
| Ruan, Hai-Bin; Ma, Yina; Torres, Sara et al. (2017) Calcium-dependent O-GlcNAc signaling drives liver autophagy in adaptation to starvation. Genes Dev 31:1655-1665 |
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