Browsing by Subject "signaling"
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Item Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging(MDPI, 2021-03-16) Yu, Mengdi; Zhang, Hongxia; Wang, Brian; Zhang, Yinuo; Zheng, Xiaoying; Shao, Bei; Zhuge, Qichuan; Jin, KunlinAging is a fundamental biological process accompanied by a general decline in tissue function. Indeed, as the lifespan increases, age-related dysfunction, such as cognitive impairment or dementia, will become a growing public health issue. Aging is also a great risk factor for many age-related diseases. Nowadays, people want not only to live longer but also healthier. Therefore, there is a critical need in understanding the underlying cellular and molecular mechanisms regulating aging that will allow us to modify the aging process for healthy aging and alleviate age-related disease. Here, we reviewed the recent breakthroughs in the mechanistic understanding of biological aging, focusing on the adenosine monophosphate-activated kinase (AMPK), Sirtuin 1 (SIRT1) and mammalian target of rapamycin (mTOR) pathways, which are currently considered critical for aging. We also discussed how these proteins and pathways may potentially interact with each other to regulate aging. We further described how the knowledge of these pathways may lead to new interventions for antiaging and against age-related disease.Item Presence of Androgen Receptor Variant in Neuronal Lipid Rafts(Society for Neuroscience, 2017-08-29) Garza-Contreras, Jo; Duong, Phong; Snyder, Brina D.; Schreihofer, Derek A.; Cunningham, Rebecca L.Fast, nongenomic androgen actions have been described in various cell types, including neurons. However, the receptor mediating this cell membrane-initiated rapid signaling remains unknown. This study found a putative androgen receptor splice variant in a dopaminergic N27 cell line and in several brain regions (substantia nigra pars compacta, entorhinal cortex, and hippocampus) from gonadally intact and gonadectomized (young and middle-aged) male rats. This putative splice variant protein has a molecular weight of 45 kDa and lacks an N-terminal domain, indicating it is homologous to the human AR45 splice variant. Interestingly, AR45 was highly expressed in all brain regions examined. In dopaminergic neurons, AR45 is localized to plasma membrane lipid rafts, a microdomain involved in cellular signaling. Further, AR45 protein interacts with membrane-associated G proteins Galphaq and Galphao. Neither age nor hormone levels altered AR45 expression in dopaminergic neurons. These results provide the first evidence of AR45 protein expression in the brain, specifically plasma membrane lipid rafts. AR45 presence in lipid rafts indicates that it may function as a membrane androgen receptor to mediate fast, nongenomic androgen actions.Item Signaling in Natural Killer Cells: NK Cell Activation by LLT1 Receptor(2008-05-01) Bambard, Nowland D.; Jerry Simecka; Richard Easom; Harlan JonesBambard, Nowland D., Signaling in Natural Killer Cells: NK Cell Activation by LLT1 Receptor. Doctor of Philosophy (Microbiology and Immunology), May 2008, 162 pp., 1 table, 30 illustrations, bibliography, 179 titles. Natural Killer (NK) cells are large granular lymphocytes of the innate immune system that constitute the first line of defense against viral pathogens and cancer. Unlink cells of the adaptive immune response, NK cells do not recognize specific antigens expressed on MHC receptors, rather they recognize tumorgenic and virally infected cells through a complex balance of activating and inhibiting receptors expressed on the surface of human NK cells. LLT1 is expressed on numerous immune cells and subsequent functional analysis indicates that LLT1 plays an activating role on NK cells by way of stimulating interferon-gamma (IFN-G) secretion. LLT1 has also been shown to have a role on non-immune cells, inhibiting the formation and function of osteoclasts. Additionally, the natural ligand of LLT1 has been identified as NKR-P1A (CD161), an NK cell inhibitory receptor known to play an important role in immune regulation. We hypothesize that LLT1 employs multiple signaling pathways to accomplish its activating functions on human NK cells, and may be associated with one of four known transmembrane accessory proteins associated with NK cell activating receptors. We activated LLT1 on NK92 cells with target cells expressing its natural ligand CD161 and analyzing IFN-G production in the presence of pharmacological inhibitors specific for various signaling mechanisms. These results indicate that LLT1 employs Src-PTK, p38 and ERK signaling pathways, but not PKC, P13K or calcineurin. These results were followed up with phosphorylation analysis, which confirmed that the ERK signaling pathway is associated with LLT1 IFN-G production. Finally, by analyzing IFN-G mRNA we found that LLT1 activation is not associated with any detectable change in IFN-G mRNA levels, suggesting that LLT1 stimulates NK IFN-G production by modulating post transcriptional or translational events. Identification of the signaling pathways associated with LLT1 is of great medical significance as this may provide us with novel insights into activating NK cells to counter infection and cancer.Item The Role of 14-3-3 in the Signaling of Cardiac Hypertrophy(2002-01-01) Ellis, Joel James; Stephen R. Grant; Neeraj Agarwall; Glenn DillonEllis, Joel J., The Role of 14-3-3 in the Signaling of Cardiac Hypertrophy. Master of Science (Biotechnology), January, 2002, 97pp., 21 illustrations, bibliography, 46 titles. The METF2 family of transcription factors is regulated by class II histone deacetylaces in the nucleus. MEF2-dependent gene expression in cardiomyocytes is augmented by the 14-3-3 chaperone family which binds and sequesters class II HDACs in the cytoplasm upon the activation of CaM kinase I & IV. A 14-3-3β mutant was made by conservatively substituting aspartate for serine 60 and serine 65. In MEF2 enhancer-reporter transfection assays, expression of the 14-3-3β double mutant silenced transcription mediated by CaM KI & IV in both cardiomyocytes and vascular smooth muscle cells. Co-expression of the 14-3-3β double mutant was also able to suppress MEF2 enhancer activation by phenylephrine in cardiomyocytes and vascular smooth muscle cells. Mammalian two-hybrid cloning of the 14-3-3β wild-type and double mutant genes will allow analysis of the protein-protein interaction between the different 14-3-3β monomers. These data suggest that 14-3-3β plays a critical role in the silencing of MEF2 mediated hypertrophy-sensitive gene transcription.