Cell cycle control in B cell terminal differentiation induced by IL-6: Repression of Epstein-Barr virus LMP1 by CDK inhibitorp18.
Item
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Title
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Cell cycle control in B cell terminal differentiation induced by IL-6: Repression of Epstein-Barr virus LMP1 by CDK inhibitorp18.
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Identifier
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AAI9917638
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identifier
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9917638
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Creator
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Chen, Dongquan.
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Contributor
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Adviser: Selina Chen-Kiang
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Date
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1999
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Language
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English
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Publisher
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City University of New York.
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Subject
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Health Sciences, Immunology | Biology, Molecular | Biology, Microbiology
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Abstract
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IL-6 induces orderly differentiation, cell cycle arrest and cell death in B cell terminal differentiation in an Epstein-Barr virus (EBV)-immortalized human IgG+ lymphoblastoid B cell line CESS. The mechanism underling this concerted process is not well understood. Here, we show that IL-6 activates the CDK inhibitor p18INK4C, leading to sequestration of CDK6 by p18 and cell cycle arrest in IgG+ CESS cells. However, IL-6 induces differentiation without cell cycle arrest in IgM+ cells. Overexpression of p18 is sufficient to reconstitute coupled differentiation and cell cycle arrest in IgM+ cells. This suggests a role for p18 in IL-6-induced cell cycle control during B cell terminal differentiation.;It has been shown that concomitant with cell cycle arrest, the EBV transforming genes EBV nuclear antigen (EBNA) 1, EBNA2 and LMP1 are suppressed in IgG+ cells. Thus, there is an inverse relationship between the expressions of p18 and EBV transforming genes, and p18 may mediate the IL-6 signals for suppression of EBV expression. To address these possibilities, we first identified that suppression of LMP1, but not EBNA2, correlated with cell cycle arrest. We then showed that expression of p18 by an adenovirus recombinant virus led to cell cycle arrest in both IgM-bearing and IgG-bearing B cells. We further demonstrated that expression of p18 alone was sufficient to cause degradation of the LMP1. Together with the finding that IL-6 induces degradation of LMP1 by a mechanism independent of the proteosomes, our results suggest that p18 mediates the IL-6 signals to suppress the expression of LMP1 by proteolysis independent of the proteosomes.;Further investigation of EBV immortalization of primary human B lymphocytes reveals that IgM+, but not IgG+, cells are preferentially immortalized by EBV, correlating with elevated LMP1 expression and continuous cell cycling. This implies that transformation of human B cells by EBV and impairment of terminal differentiation may hinge on LMP1 expression, which in turn appears to be contingent on the B cell developmental stages. Therefore, we propose that IL-6 signals a critical interplay between p18 and the LMP1 protein that simultaneously reverses EBV transformation and induces cell cycle arrest, the hallmark of B cell terminal differentiation.
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Type
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dissertation
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Source
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PQT Legacy CUNY.xlsx
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degree
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Ph.D.
