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The Notch negative regulatory region...

Malecki, Michael John.

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The Notch negative regulatory region: Mutations and mechanisms.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The Notch negative regulatory region: Mutations and mechanisms./
Author:	Malecki, Michael John.
Description:	156 p.
Notes:	Adviser: Stephen C. Blacklow.
Contained By:	Dissertation Abstracts International68-05B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3265031
ISBN:	9780549042938

The Notch negative regulatory region: Mutations and mechanisms.
Malecki, Michael John.

The Notch negative regulatory region: Mutations and mechanisms. - 156 p.

Adviser: Stephen C. Blacklow.

Thesis (Ph.D.)--Harvard University, 2007.

Notch signaling is a developmentally conserved pathway involved in cell fate determination. One development program in which Notch signaling plays a prominent role is in the development of the immune system, where Notch1, one of four mammalian Notch receptors, guides the choice of T-cell fate. However, mutations leading to aberrant increases in Notch1 signaling are associated with T-cell Acute Lymphoblastic Leukemia (T-ALL), indicating the importance of regulation in modulating the timing and strength of Notch1 signals.

ISBN: 9780549042938Subjects--Topical Terms:

1017686
Biology, Cell.

The Notch negative regulatory region: Mutations and mechanisms.
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020 $a 9780549042938
035 $a (UMI)AAI3265031
035 $a AAI3265031
040 $a UMI $c UMI
100 1 $a Malecki, Michael John. $3 1285765
245 1 4 $a The Notch negative regulatory region: Mutations and mechanisms.
300 $a 156 p.
500 $a Adviser: Stephen C. Blacklow.
500 $a Source: Dissertation Abstracts International, Volume: 68-05, Section: B, page: 3031.
502 $a Thesis (Ph.D.)--Harvard University, 2007.
520 $a Notch signaling is a developmentally conserved pathway involved in cell fate determination. One development program in which Notch signaling plays a prominent role is in the development of the immune system, where Notch1, one of four mammalian Notch receptors, guides the choice of T-cell fate. However, mutations leading to aberrant increases in Notch1 signaling are associated with T-cell Acute Lymphoblastic Leukemia (T-ALL), indicating the importance of regulation in modulating the timing and strength of Notch1 signals.
520 $a Notch receptors are synthesized as single-chain type-I transmembrane proteins. During transit through the trans-golgi, Notch receptors are typically cleaved by a furin-like protease, resulting in two subunits that are non-covalently associated through a subunit heterodimerization (HD) domain. The majority of leukemia-associated mutations in human Notch1, which are found in about 40% of T-ALLs, lie in this HD domain.
520 $a This dissertation aims to understand the events surrounding maintenance of Notch receptors in the "off" state and those surrounding activation of these receptors by leukemia-associated mutations. Chapter two describes the classification of these HD mutations by biochemical and functional means. HD mutations activate Notch in a ligand-independent but protease-dependant manner and segregate into at least two mechanistic classes. Chapter three describes the cellular context of these mutations. HD mutations cause Notch receptors to become trapped in the endoplasmic reticulum, but a small fraction of molecules reach the plasma membrane, whereupon they are efficiently and autonomously activated. Chapter four answers key questions in the field surrounding the role of furin cleavage. Notch receptors that are unable to be cleaved by the protease furin were developed, and the structure and function of these receptors is indistinguishable from wild-type. Finally, chapter five describes initial efforts to form a complex between Notch and its ligands for biochemical and biophysical characterization. Together, these studies provide new understanding on how Notch receptors are regulated normally and dysregulated by leukemia-associated mutations.
590 $a School code: 0084.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Chemistry, Biochemistry. $3 1017722
650 4 $a Health Sciences, Oncology. $3 1018566
690 $a 0379
690 $a 0487
690 $a 0992
710 2 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 68-05B.
790 $a 0084
790 1 0 $a Blacklow, Stephen C., $e advisor
791 $a Ph.D.
792 $a 2007
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3265031