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Dissertation
Serotonin is an autocrine-paracrine survival factor for human acute T leukemic cells
Doctor of Philosophy (Ph.D.), Drexel University
Sep 2005
DOI:
https://doi.org/10.17918/00008612
Abstract
Serotonin (5-HT) is a critical multi-faceted bioamine that is generally synthesized in serotoninergic neurons of the central nervous system and in enterochromaffin cells in the gastrointestinal tract. It functions as a neurotransmitter, a vasoactive factor, an immune modulator and a growth/survival factor in the human body. This thesis provides evidence that serotonin and its receptors are present and functional in T leukemic cells. We have identified the presence of tryptophan hydroxylase (TPH1) (the rate-limiting enzyme involved in the metabolic conversion of tryptophan to serotonin) in CEM and Jurkat cells by RT-PCR and immunofluorescence methods. We have also evaluated its enzymatic activity by quantification of secreted 5-HT in the culture supernatants by HPLC-EC. Moreover, multiple 5-HT receptor subtypes have been detected on CEM and Jurkat cells by RT-PCR and Southern blot, including the 5-HT1A & 1B and three 5-HT2 receptor subtypes. Finally, published reports have shown that 5-HT regulates human PBMCs proliferation and cytokine secretion. Based on these observations, we propose that 5-HT may act as an autocrine-paracrine growth/survival factor for T leukemic cells. We have successfully identified the 5-HT1B receptor, from the fourteen pharmacologically distinct 5-HT receptor subtypes, as the key receptor regulating T cell growth and preventing T cell apoptosis through activating the P13K/Akt signaling pathway. We have also shown that the highly selective classical 5-HT1A antagonist Pindobind-5-HT1A, but not WAY-100635 and p-MPPF, can inhibit T leukemic cell proliferation and induce apoptosis through a non-classical 5-HT1A receptor coupled signaling pathway, which indicates that Pindobind-5-HT1A may interact with a novel "5-HT-related" receptor to execute its inhibitory effect on T leukemic cells. Future studies will focus on identification of this novel "5-HT-related" receptor and clarification of its molecular functional mechanism. Taken together, our data demonstrate that 5-HT is an autocrine-paracrine survival factor for human T leukemic cells. Antagonism of 5-HT1B receptor may provide a new clinical strategy to treat T cell leukemias and other immune disorders.
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Details
- Title
- Serotonin is an autocrine-paracrine survival factor for human acute T leukemic cells
- Creators
- Jun Yin
- Contributors
- Bradford Aldrich Jameson (Advisor) - Drexel University, Drexel University (1970-)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xv, 197 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991021888973304721