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Inhibition of isoprenylcysteine carb...

Duke University.

Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis.

Record Type:	Electronic resources : Monograph/item
Title/Author:	Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis.
Author:	Winter-Vann, Ann Marie.
Description:	159 p.
Notes:	Source: Dissertation Abstracts International, Volume: 65-06, Section: B, page: 2741.
Notes:	Supervisor: Patrick J. Casey.
Contained By:	Dissertation Abstracts International65-06B.
Subject:	Biology, Cell.
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3136841
ISBN:	0496840371

Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis.
Winter-Vann, Ann Marie.

Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis. - 159 p.

Source: Dissertation Abstracts International, Volume: 65-06, Section: B, page: 2741.

Thesis (Ph.D.)--Duke University, 2004.

Carboxyl methylation of Ras is clearly important for proper plasma membrane localization and function. Cellular methylation is inhibited by S-adenosylhomocysteine (AdoHcy), a product of methylation reactions that utilize S-adenosylmethionine as a methyl donor. Because AdoHcy is elevated following treatment with the classic chemotherapy drug methotrexate, we investigated the impact of methotrexate treatment on Icmt-catalyzed methylation. Following methotrexate treatment of DKOB8 cells, Ras methylation is decreased by almost 90%. This hypomethylation is accompanied by a mislocalization of Ras to the cytosol and a four-fold decrease in the activation of downstream effectors. Additionally, cells lacking Icmt are highly resistant to methotrexate. While cells expressing Icmt are inhibited by methotrexate, stable expression of myristoylated H-Ras, which does not require carboxyl methylation for membrane attachment, confers resistance to methotrexate. These results suggest that inhibition of Icmt is a critical component of the anti proliferative effect of methotrexate.

ISBN: 0496840371Subjects--Topical Terms:

226967
Biology, Cell.

Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis.
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245 1 0 $a Inhibition of isoprenylcysteine carboxyl methyltransferase: A new (old) target in oncogenesis.
300 $a 159 p.
500 $a Source: Dissertation Abstracts International, Volume: 65-06, Section: B, page: 2741.
500 $a Supervisor: Patrick J. Casey.
502 $a Thesis (Ph.D.)--Duke University, 2004.
520 # $a Carboxyl methylation of Ras is clearly important for proper plasma membrane localization and function. Cellular methylation is inhibited by S-adenosylhomocysteine (AdoHcy), a product of methylation reactions that utilize S-adenosylmethionine as a methyl donor. Because AdoHcy is elevated following treatment with the classic chemotherapy drug methotrexate, we investigated the impact of methotrexate treatment on Icmt-catalyzed methylation. Following methotrexate treatment of DKOB8 cells, Ras methylation is decreased by almost 90%. This hypomethylation is accompanied by a mislocalization of Ras to the cytosol and a four-fold decrease in the activation of downstream effectors. Additionally, cells lacking Icmt are highly resistant to methotrexate. While cells expressing Icmt are inhibited by methotrexate, stable expression of myristoylated H-Ras, which does not require carboxyl methylation for membrane attachment, confers resistance to methotrexate. These results suggest that inhibition of Icmt is a critical component of the anti proliferative effect of methotrexate.
520 # $a Much research on the importance of Icmt-catalyzed methylation in biology has relied upon relatively non-specific inhibitors that clearly have pleiotropic effects on cells. Recent work from our lab has identified a small molecule inhibitor that exhibits higher specificity toward Icmt. This indole-based compound, termed 9J20, inhibits the growth of cells in an Icmt-dependent manner. Treatment with 9J20 decreases Ras carboxylmethylation, causes a dose dependent mislocalization of Ras and inhibits signaling through Ras pathways. Finally, 9J20 decreases anchorage dependent growth at concentrations that only marginally affect cell growth. Together with the finding that methotrexate targets Icmt, these results suggest that small molecule inhibitors of Icmt may be effective as cancer chemotherapeutics.
520 # $a Ras GTPases and many other important regulatory proteins contain a C-terminal CaaX motif that signals the addition of an isoprenoid lipid. Following prenylation of the CaaX cysteine, the C-terminal three amino acids are proteolytically removed and the C-terminal prenylcysteine is methylated by the CaaX methyltransferase, Icmt. Although prenyl groups act as membrane anchors, the role of prenylcysteine methylation is not well understood. This modification aids in membrane association by making the C-terminus more hydrophobic, but it can also affect the stability of substrate proteins. Additionally, carboxylmethylation may be important in specific protein-protein interactions, and regulation of this event may add another level of control to signaling pathways.
590 $a School code: 0066.
650 # 0 $a Biology, Cell. $3 226967
650 # 0 $a Biology, Molecular. $3 226919
650 # 0 $a Chemistry, Biochemistry. $3 226900
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690 $a 0379
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710 0 # $a Duke University. $3 226880
773 0 # $g 65-06B. $t Dissertation Abstracts International
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