Browsing by Subject "Mitogens"
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Item P38 MAPKs coordinately regulate distinct phases of autophagy and lysomal biogenesis(2008-08) Varadarajan, Shankar; Bratton, Shawn B.p38 mitogen-activated protein kinases (MAPKs) control the endocytic trafficking of various growth-related cell surface receptors and transporters. Herein, I demonstrate that p38 MAPKs also regulate autophagy, or the process of self-cannibalism. In my studies, inhibition of p38 MAPKs triggered rapid formation of autophagosomes in prostate cancer cells, even under nutrient-rich conditions, and remarkably, the autophagosomal membranes emanated from endoplasmic reticulum exit sites via the concerted actions of the small GTPases, ARF1 and SAR1. Once formed, the autophagosomes fused with late endosomes and/or lysosomes, in a Rab7-dependent manner, to form “hybrid organelles” that were co-labeled with ER, autophagic, late endosomal, and lysosomal markers. Unlike other inducers of autophagy, however, inhibition of p38 MAPKs suppressed the fission of hybrid organelles, resulting in a profound but reversible accumulation of large cytoplasmic vacuoles. Thus, in addition to their previously reported roles in endocytosis, p38 MAPKs appear to coordinately regulate autophagy and the downstream biogenesis and fission of hybrid organelles.Item Role of I Kappa B Kinase Alpha and I Kappa B Kinase Beta in the Development and Function of B and T Lymphocytes(2002-08-22) Ren, Hong; Gaynor, Richard B.Phenotypic analysis of transgenic mice expressing dominant negative IKKᠩn the B cells revealed that the proliferation of B cells from these mutant mice in response to B cell mitogens was reduced due to impaired cell cycle progression. Accordingly, in vitro secretion of immunoglobulins by the mutant B cells in response to these mitogens was also decreased. In addition, these mice displayed selective defects in the production of specific immunoglobulin subclasses in response to type 2 but not type 1 T cell independent antigens. Moreover, the levels of certain immunoglobulin subclasses were reduced in mutant mice challenged with a T cell dependent antigen. These results indicate that IKKᠩs critical for the proliferation of B cells and the control of some aspects of the humoral response. Transgenic mice expressing one or both of the dominant negative IKK specifically in T cells exhibited distinct phenotypes in thymocyte proliferation, cytokine production, and cell survival. Proliferation of thymic T cells from IKKᠭutant mice and IKKa/ᠭutant mice was markedly reduced due to impaired cell cycle progression. In addition, inhibition of both IKKa and IKKᠡppeared to suppress the expression of multiple cytokines by thymocytes. Furthermore, apoptosis of the double positive thymocytes induced by the administration of anti-CD3 antibody was significantly reduced in transgenic mice expressing dominant negative IKKᬠbut increased in mice expressing only dominant negative IKKa. These results indicate that IKKa and IKKᠰlay different roles in regulating the activation and survival of T cells.