國立高雄大學圖資館 |

Language: English

Back

Functional and biochemical character...

Harvard University.

Functional and biochemical characterization of the negative regulatory region of mammalian Notch.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Functional and biochemical characterization of the negative regulatory region of mammalian Notch.
Author:	Sanchez-Irizarry, Cheryll.
Description:	118 p.
Notes:	Adviser: Stephen C. Blacklow.
Notes:	Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0712.
Contained By:	Dissertation Abstracts International67-02B.
Subject:	Biology, Molecular.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205949
ISBN:	9780542549526

Functional and biochemical characterization of the negative regulatory region of mammalian Notch.
Sanchez-Irizarry, Cheryll.

Functional and biochemical characterization of the negative regulatory region of mammalian Notch. - 118 p.

Adviser: Stephen C. Blacklow.

Thesis (Ph.D.)--Harvard University, 2006.

A N&barbelow;egative R&barbelow;egulatory R&barbelow;egion (NRR) is responsible for maintaining Notch heterodimers in a resting conformation in the absence of ligand. The NRR resides entirely external to the membrane, encompassing the LNR repeats of NEC and a novel domain divided by furin cleavage. This thesis describes functional, biochemical, and biophysical studies of the NRR focusing on the following questions: (i) how do the LNR and the novel domain prevent premature activation of Notch receptors, and (ii) how do leukemia-derived mutations within the Notch1 NRR lead to increased levels of signaling?

ISBN: 9780542549526Subjects--Topical Terms:

226919
Biology, Molecular.

Functional and biochemical characterization of the negative regulatory region of mammalian Notch.
LDR:03540nmm _2200301 _450 001 180469
005 20080111103711.5
008 090528s2006 eng d
020 $a 9780542549526
035 $a 00311492
040 $a UMI $c UMI
100 0 $a Sanchez-Irizarry, Cheryll. $3 264044
245 1 0 $a Functional and biochemical characterization of the negative regulatory region of mammalian Notch.
300 $a 118 p.
500 $a Adviser: Stephen C. Blacklow.
500 $a Source: Dissertation Abstracts International, Volume: 67-02, Section: B, page: 0712.
502 $a Thesis (Ph.D.)--Harvard University, 2006.
520 # $a A N&barbelow;egative R&barbelow;egulatory R&barbelow;egion (NRR) is responsible for maintaining Notch heterodimers in a resting conformation in the absence of ligand. The NRR resides entirely external to the membrane, encompassing the LNR repeats of NEC and a novel domain divided by furin cleavage. This thesis describes functional, biochemical, and biophysical studies of the NRR focusing on the following questions: (i) how do the LNR and the novel domain prevent premature activation of Notch receptors, and (ii) how do leukemia-derived mutations within the Notch1 NRR lead to increased levels of signaling?
520 # $a Chapter Two shows that the LNR and the novel region have different roles in regulating the activity of Notch receptors. The LNR is necessary for preventing premature proteolytic activation, whereas the novel domain is responsible for holding the furin-cleaved subunits together as a heterodimer (hereafter HD, for heterodimerization domain). These findings facilitated the discovery by collaborators in the Aster group that missense mutations in HD occur frequently in primary human T-ALLs. Chapter Three reports biochemical and functional analysis of fifteen leukemia-associated mutations scattered throughout the HD, showing that HD mutations of human Notch1 induce ligand-independent increases in signaling by either promoting subunit dissociation, or by directly exposing the metalloprotease cleavage site. Chapter Four reports preliminary biophysical analysis of mammalian HDs, showing that furin cleavage does not promote major conformational changes. Together, these studies provide new insight into the biochemistry underlying regulation of Notch receptor activation.
520 # $a During maturation, mammalian Notch receptors are cleaved by a furin-like convertase, yielding a heterodimer between extracellular (NEC) and transmembrane (NTM) subunits. Signaling is typically activated when ligands bind to NEC, and trigger a series of proteolytic cleavages in NTM, releasing the intracellular portion of NTM (ICN) into the nucleus to upregulate transcription of target genes.
520 # $a Notch receptors constitute a family of highly conserved transmembrane receptors that transduce signals between neighboring cells during the development of multicellular organisms. This thesis focuses primarily on human Notch1, one of four mammalian Notch receptors. Though Notch1 signals are normally required for proper T-cell development, gain-of-function mutations in Notch1 lead to T-ALL both in humans and in mouse models.
590 $a School code: 0084.
650 # 0 $a Biology, Molecular. $3 226919
650 # 0 $a Chemistry, Biochemistry. $3 226900
690 $a 0307
690 $a 0487
710 0 # $a Harvard University. $3 212445
773 0 # $g 67-02B. $t Dissertation Abstracts International
790 $a 0084
790 1 0 $a Blacklow, Stephen C., $e advisor
791 $a Ph.D.
792 $a 2006
856 4 0 $u http://libsw.nuk.edu.tw:81/login?url=http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205949 $z http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3205949