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Activation of the Abl tyrosine kinas...

Smith, Kristen Michelle.

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Activation of the Abl tyrosine kinase by oligomerization.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	Activation of the Abl tyrosine kinase by oligomerization./
Author:	Smith, Kristen Michelle.
Description:	182 p.
Notes:	Adviser: Richard A. Van Etten.
Contained By:	Dissertation Abstracts International63-04B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051293
ISBN:	049365867X

Activation of the Abl tyrosine kinase by oligomerization.
Smith, Kristen Michelle.

Activation of the Abl tyrosine kinase by oligomerization. - 182 p.

Adviser: Richard A. Van Etten.

Thesis (Ph.D.)--Harvard University, 2002.

To investigate the sufficiency of dimerization for Abl kinase activation, I utilized a conditional system of oligomerization. This system consists a chemical dimerizer, a compound with two binding surfaces that can bind simultaneously to two protein targets, and a target domain that binds the dimerizing ligand (FKBP). A chimeric Abl-FKBP protein was constructed and characterized in a variety of cellular transformation assays. Using this system I demonstrated that oligomerization was sufficient to activate the Abl kinase <italic>in vivo</italic> and induce transformation of fibroblasts and hematopoeitic cells. This system could be a useful tool for investigating the primary consequences of activating Abl kinase <italic>in vivo</italic> as well as understanding the regulation of c-Abl.

ISBN: 049365867XSubjects--Topical Terms:

1017686
Biology, Cell.

Activation of the Abl tyrosine kinase by oligomerization.
LDR:03735nam 2200325 a 45 001 927774
005 20110425
008 110425s2002 eng d
020 $a 049365867X
035 $a (UnM)AAI3051293
035 $a AAI3051293
040 $a UnM $c UnM
100 1 $a Smith, Kristen Michelle. $3 1251337
245 1 0 $a Activation of the Abl tyrosine kinase by oligomerization.
300 $a 182 p.
500 $a Adviser: Richard A. Van Etten.
500 $a Source: Dissertation Abstracts International, Volume: 63-04, Section: B, page: 1653.
502 $a Thesis (Ph.D.)--Harvard University, 2002.
520 $a To investigate the sufficiency of dimerization for Abl kinase activation, I utilized a conditional system of oligomerization. This system consists a chemical dimerizer, a compound with two binding surfaces that can bind simultaneously to two protein targets, and a target domain that binds the dimerizing ligand (FKBP). A chimeric Abl-FKBP protein was constructed and characterized in a variety of cellular transformation assays. Using this system I demonstrated that oligomerization was sufficient to activate the Abl kinase <italic>in vivo</italic> and induce transformation of fibroblasts and hematopoeitic cells. This system could be a useful tool for investigating the primary consequences of activating Abl kinase <italic>in vivo</italic> as well as understanding the regulation of c-Abl.
520 $a While the characterization of Abl-FKBP chimeric proteins suggests that oligomerization is sufficient for kinase activation, it did not exclude a role for other Bcr domains for transformation and leukemogenesis by Bcr-Abl. To investigate the effects of oligomerization on Bcr-Abl, I replaced the coiled-coil domain of Bcr with FKBP to create a Bcr-Abl-FKBP chimera that could be inducibly dimerized. Like Abl-FKBP, the chimeric proteins were able to induce kinase activation and transformation of fibroblasts, hematopoetic cells, and primary B-lymphoid cells in a ligand-dependent manner. These results suggest the Bcr-Abl-FKBP conditional mutant will be a valuable reagent for studying the mechanism of cellular transformation and resistance to apoptosis induced by Bcr-Abl, and may be useful for generation of conditional animal models of Ph<super>1</super> positive leukemia, particularly by transgenic approaches.
520 $a I generated a Bcr mutant with alanines substituted for the hydrophobic residues of the coiled-coil domain, a second mutant with substitution of a single proline in the middle of the domain, and a third mutant lacking the coiled-coil domain. Results suggest that oligomerization of Bcr-Abl stimulates Abl kinase activity by promoting intermolecular autophosphorylation, but abrogation of the intramolecular inhibitory function of the SH3 domain can substitute for oligomerization.
520 $a Paradoxically, the proline substitution mutant transformed fibroblasts and primary B cells <italic>in vitro</italic> and efficiently induced B-lymphoid leukemia instead of CML-like disease in mice. Myeloid leukemogenesis was partially restored by SH3 mutation. This mutant may retain some oligomerization activity <italic> in vivo</italic> although it was not detected in a coprecipitation assay. I also identified a revertant of a Bcr-Abl coiled-coil mutant that efficiently transforms fibroblasts, and localized the reversion mutation to a novel region in the Abl COOH-terminus. (Abstract shortened by UMI.)
590 $a School code: 0084.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Molecular. $3 1017719
650 4 $a Health Sciences, Oncology. $3 1018566
690 $a 0307
690 $a 0379
690 $a 0992
710 2 0 $a Harvard University. $3 528741
773 0 $t Dissertation Abstracts International $g 63-04B.
790 $a 0084
790 1 0 $a Van Etten, Richard A., $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3051293