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The biological significance and mole...

University of California, Los Angeles.

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The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways./
Author:	Zarnegar, Brian John.
Description:	109 p.
Notes:	Adviser: Genhong Cheng.
Contained By:	Dissertation Abstracts International69-02B.
Subject:	Biology, Molecular. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoeng/servlet/advanced?query=3302574
ISBN:	9780549484233

The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways.
Zarnegar, Brian John.

The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways. - 109 p.

Adviser: Genhong Cheng.

Thesis (Ph.D.)--University of California, Los Angeles, 2008.

The NF-kappaB family of transcription factors makes tremendous contributions to an array of biological responses including the initiation and propagation of both innate and adaptive immune responses. Recent years have separated NF-kappaB signaling into two distinct activation pathways. Activation of the canonical NF-kappaB pathway results from activation of the IKK complex which leads to the nuclear translocation of p50-containg NF-kappaB complexes. Activation of the noncanonical NF-kappaB pathway, in contrast, results from the activation of NIK which leads to the nuclear translocation of p52-containing NF-kappaB complexes. Importantly, deregulation of either NF-kappaB activation pathway contributes to numerous diseases including multiple cancers. Many members of the Tumor Necrosis Factor Receptor (TNFR) superfamily are capable of activating both the canonical and noncanonical NF-kappaB pathways. Here, we first demonstrate that the unique biological power of CD40 in B-lymphocyte activation results directly from simultaneous activation of both NF-kappaB signaling pathways. Importantly, the TRAF family of adaptor proteins provides an essential link between the TNFRs and the activation of the canonical and noncanonical NF-kappaB pathways. Significantly, all TNFR family members that are capable of binding TRAF3 also activate the noncanonical NF-kappaB signaling pathway. Here we demonstrate that TRAF3 functions as an essential negative regulator of the noncanonical NF-kappaB pathway by direct suppression of NIK. Remarkably, we also show that the early post natal lethality caused by loss of TRAF3 can be rescued by compound loss NIK. Surprisingly, we also found that TRAF3 functions as a potent suppressor of the canonical NF-kappaB pathway and demonstrate that TRAF3 negatively regulates canonical NF-kappaB activity through direct negative regulation of the IKK complex. Finally, we show that negative regulation of NIK also requires TRAF2. Importantly, we demonstrate that while TRAF2 and TRAF3 are both required for suppressing NIK, they are also insufficient. Here, we demonstrate that TRAF2 and TRAF3 recruitment the ubiquitin ligases cIAP1 and cIAP2 to NIK and that inhibition of cIAP1 and cIAP2 results in full activation of the noncanonical NF-kappaB pathway. Thus, we propose a new model in which TRAF2 and TRAF3 coordinate the destruction of NIK by recruitment of cIAP1 and cIAP2.

ISBN: 9780549484233Subjects--Topical Terms:

1017719
Biology, Molecular.

The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways.
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100 1 $a Zarnegar, Brian John. $3 1025223
245 1 4 $a The biological significance and molecular mechanism of TRAF3 suppression of the canonical and noncanonical NF-kappaB activation pathways.
300 $a 109 p.
500 $a Adviser: Genhong Cheng.
500 $a Source: Dissertation Abstracts International, Volume: 69-02, Section: B, page: 0848.
502 $a Thesis (Ph.D.)--University of California, Los Angeles, 2008.
520 $a The NF-kappaB family of transcription factors makes tremendous contributions to an array of biological responses including the initiation and propagation of both innate and adaptive immune responses. Recent years have separated NF-kappaB signaling into two distinct activation pathways. Activation of the canonical NF-kappaB pathway results from activation of the IKK complex which leads to the nuclear translocation of p50-containg NF-kappaB complexes. Activation of the noncanonical NF-kappaB pathway, in contrast, results from the activation of NIK which leads to the nuclear translocation of p52-containing NF-kappaB complexes. Importantly, deregulation of either NF-kappaB activation pathway contributes to numerous diseases including multiple cancers. Many members of the Tumor Necrosis Factor Receptor (TNFR) superfamily are capable of activating both the canonical and noncanonical NF-kappaB pathways. Here, we first demonstrate that the unique biological power of CD40 in B-lymphocyte activation results directly from simultaneous activation of both NF-kappaB signaling pathways. Importantly, the TRAF family of adaptor proteins provides an essential link between the TNFRs and the activation of the canonical and noncanonical NF-kappaB pathways. Significantly, all TNFR family members that are capable of binding TRAF3 also activate the noncanonical NF-kappaB signaling pathway. Here we demonstrate that TRAF3 functions as an essential negative regulator of the noncanonical NF-kappaB pathway by direct suppression of NIK. Remarkably, we also show that the early post natal lethality caused by loss of TRAF3 can be rescued by compound loss NIK. Surprisingly, we also found that TRAF3 functions as a potent suppressor of the canonical NF-kappaB pathway and demonstrate that TRAF3 negatively regulates canonical NF-kappaB activity through direct negative regulation of the IKK complex. Finally, we show that negative regulation of NIK also requires TRAF2. Importantly, we demonstrate that while TRAF2 and TRAF3 are both required for suppressing NIK, they are also insufficient. Here, we demonstrate that TRAF2 and TRAF3 recruitment the ubiquitin ligases cIAP1 and cIAP2 to NIK and that inhibition of cIAP1 and cIAP2 results in full activation of the noncanonical NF-kappaB pathway. Thus, we propose a new model in which TRAF2 and TRAF3 coordinate the destruction of NIK by recruitment of cIAP1 and cIAP2.
590 $a School code: 0031.
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650 4 $a Health Sciences, Immunology. $3 1017716
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710 2 $a University of California, Los Angeles. $3 626622
773 0 $t Dissertation Abstracts International $g 69-02B.
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790 1 0 $a Cheng, Genhong, $e advisor
791 $a Ph.D.
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