Browsing by Subject "calcium signaling"
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Item Effect of CD44 Expression on T Cell Acute Lymphocytic Leukemia(2014-08-01) Racine, Ronny R.; Mummert, Mark E.; Jones, Harlan; Berg, Rance E.CD44 is a cell surface glycoprotein that serves as a multifunctional receptor aiding in trafficking and adhesion of immune cells. CD44 also serves as a recruitment platform for signaling molecules and has been shown to regulate proliferation. In several types of leukemia the presence or absence of CD44 expression is associated with different clinical outcomes, with patients who have increased expression of CD44 exhibiting a stronger response to conventional chemo- and radiotherapy. By using Jurkat T cells, which do not express CD44, to determine the effects of CD44 expression in a model Acute Lymphocytic Leukemia cell line, we have outlined two major areas of study. Firstly, upon expression of CD44, Jurkat T cells proliferate slowly compared to the control cells. This decrease in proliferation is coupled to an arrest in the cell cycle during the transition from the G1 phase into S phase. The dysregulation of the cell cycle induced by CD44 also leads to the induction of aneuploidy. CD44 expressing Jurkat T cells have reduced mRNA expression for several key regulators of chromosome separation and the mitotic spindle complex. This finding, coupled with decreased EGR-1 expression, which controls the cyclins responsible for transition from G1 into S phase, leads to an unstable cell phenotype which proliferates slowly and accumulates extra chromosomes in daughter cells. The second area of study focuses on the mechanism by which CD44 expression at the cell surface results in the observed decreases in proliferation, Akt activation, and EGR-1 expression. We observed that CD44 expressing Jurkat cells show four to five times higher calcium influx when at rest compared to the vector control cells. This influx in calcium is due to CD44 expression activating a cell surface inducible calcium release activated calcium channel. The excess calcium activates calcium-activated phosphatases and kinases, disrupting EGR-1 expression and inducing a hypophosphorylation of Akt. Together, these findings indicate that CD44 expression can regulate cell proliferation and signal transduction pathways in addition to its role in adhesion. Thus, our data provide a further understanding of how CD44 expression modifies leukemic cells into cells that are favorable for therapeutic intervention.Item Effect of Progesterone on Calcium Signaling of Hippocampal Neurons(2006-05-01) Hwang, Ji-Yeon; Koulen; Singh, Meharvan; Yang, ShaohuaJi-yeon Hwang, Effects of Progesterone on Calcium Signaling of Hippocampal Neurons. Master of Science (Pharmacology and Neuroscience), May 2006, 74 pp., 18 Figures. Progesterone (P4) is one of the steroid hormones responsible for female sexual behavior. It has been recently show that P4 plays also multiple roles in the central nervous system (CNS) including neuroprotection. Calcium (Ca2+) is involved in numerous cellular processes in nerve cells such as neurotransmitter release and cell death. In the present studies, we present evidence that P4 increases the activity of IP3R-mediated Ca2+ release within nerve cells leading to cell survival and neuroprotection. The purpose of the present study is to identify the subcellular distribution of all IP3Rs and other signaling proteins including Akt and phosphor-Akt, in the primary hippocampal neuron and to test the hypothesis that P4 controls the gain of IP3R-mediated intracellular Ca2+ signaling in neurons. We observed that primary hippocampal neurons express predominantly IP3R type 1, 2, and 3. The cellular distribution of all IP3R isoforms as well as Akt and phospho-Akt was increased in primary hippocampal neurons by P4 treatment. In addition, phospho-Akt was translocated to nucleus in response to P4. P4-pretreated neurons showed potentiated IP3R-mediated intracellular Ca2+ responses. Acute application of P4 resulted in transient elevations of intracellular Ca2+ concentrations. Our results will contribute to establishing potential pharmacological approaches for the treatment of pathological conditions characterized by a dysregulation of cellular Ca2+ concentrations such as Alzheimer’s disease.