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Dysregulated CD40-NF-kappaB signalin...

Pham, Lan.

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Dysregulated CD40-NF-kappaB signaling in the pathophysiology of aggressive non-Hodgkin's lymphoma B cells.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Dysregulated CD40-NF-kappaB signaling in the pathophysiology of aggressive non-Hodgkin's lymphoma B cells./
Author:	Pham, Lan.
Description:	176 p.
Notes:	Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0726.
Contained By:	Dissertation Abstracts International66-02B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3163231
ISBN:	0496971638

Dysregulated CD40-NF-kappaB signaling in the pathophysiology of aggressive non-Hodgkin's lymphoma B cells.
Pham, Lan.

Dysregulated CD40-NF-kappaB signaling in the pathophysiology of aggressive non-Hodgkin's lymphoma B cells. - 176 p.

Source: Dissertation Abstracts International, Volume: 66-02, Section: B, page: 0726.

Thesis (Ph.D.)--The University of Texas Graduate School of Biomedical Sciences at Houston, 2005.

Non-Hodgkin's Lymphomas (NHL) are a group (>30) of important human lymphoid cancers that unlike other tumors today, are showing a marked increase in incidence. The lack of insight to the pathogenesis of B-cell NHL poses a significant problem in the early detection and effective treatment of these malignancies. This study shows that large B-cell lymphoma (LBCL) cells, the most common type of B-cell NHL (account for more than 30% of cases), have developed a novel mechanism for autonomous neoplastic B cell growth. We have identified that the key transcription factor NF-kappaB, is constitutively activated in LBCL cell lines and primary biopsy-derived LBCL cells, suggesting that they are autonomously activated, and do not require accessory T-cell signaling for cell growth and survival. Further studies have indicated that LBCL cells ectopically express an important T-cell associated co-mitogenic factor, CD154 (CD40 ligand), that is able to internally activate the CD401NF-kappaB pathway, through constitutive binding to its cognate receptor, CD40, on the lymphoma cell surface. CD40 activation triggers the formation of a "Signalosome" comprising virtually the entire canonical CD40/NF-kappaB signaling pathway that is anchored by CD40 in plasma membrane lipid rafts. The CD40 Signalosome is vulnerable to interdiction by antibody against CD40 that disrupts the Signalosome and induces cell death in the malignant cells. In addition to constitutive NF-kappaB activation, we have found that the nuclear factor of activated T cells (NFAT) transcription factor is also constitutively activated in LBCL cells. We have demonstrated that the constitutively active NFATc1 and c-rel members of the NFAT and NF-kappaB families of transcription factors, respectively, interact with each other, bind to the CD154 promoter, and synergistically activate CD154 gene transcription. Down-regulation of NFATc1 and c-rel with small interfering RNA inhibits CD154 gene transcription and lymphoma cell growth. Our findings suggest that continuous CD40 activation not only provides dysregulated proliferative stimuli for lymphoma cell growth and extended tumor cell survival, but also allows continuous regeneration of the CD40 ligand in the lymphoma cell and thereby recharges the system through a positive feedback mechanism. Targeting the CD40/NF-kappaB signaling pathway could provide potential therapeutic modalities for LBCL cells in the future.

ISBN: 0496971638Subjects--Topical Terms:

1017719
Biology, Molecular.

Dysregulated CD40-NF-kappaB signaling in the pathophysiology of aggressive non-Hodgkin's lymphoma B cells.
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