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The role of two Rho GTPases, Cdc42 a...

Dao, Kim-Hien T.

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The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts.

Record Type:	Language materials, printed : Monograph/item
Title/Author:	The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts./
Author:	Dao, Kim-Hien T.
Description:	218 p.
Notes:	Adviser: J. Justin McCormick.
Contained By:	Dissertation Abstracts International63-09B.
Subject:	Biology, Cell. -
Online resource:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3064216
ISBN:	0493830073

The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts.
Dao, Kim-Hien T.

The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts. - 218 p.

Adviser: J. Justin McCormick.

Thesis (Ph.D.)--Michigan State University, 2002.

It is well established that carcinogenesis is a multistep process involving repeated selection and clonal expansion of cells that acquire the ability to proliferate and function uncontrollably as a result of genetic mutations. Increased activation of Rho GTPases, a subfamily of the Ras superfamily of small G-proteins, has been shown to confer cells with certain growth properties characteristic of malignant cells. However, the specific contribution of Rho GTPases to the malignant transformation of human fibroblasts has not been determined. My research emphasis has been to investigate the role of two members of the Rho subfamily, Cdc42 and Rac1, in the malignant transformation of human fibroblasts. Cdc42 and Rac1 were studied in parallel because they often act in the same pathways to regulate transcription of genes, cell cycle progression, cell differentiation, survival and apoptosis pathways, and membrane trafficking. For my studies, I chose two tumor-derived cell lines generated from the human fibroblast MSU1 cell lineage that display increased Cdc42 and Rac1 activity.

ISBN: 0493830073Subjects--Topical Terms:

1017686
Biology, Cell.

The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts.
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100 1 $a Dao, Kim-Hien T. $3 1251083
245 1 0 $a The role of two Rho GTPases, Cdc42 and Rac1, in the malignant transformation of human fibroblasts.
300 $a 218 p.
500 $a Adviser: J. Justin McCormick.
500 $a Source: Dissertation Abstracts International, Volume: 63-09, Section: B, page: 4009.
502 $a Thesis (Ph.D.)--Michigan State University, 2002.
520 $a It is well established that carcinogenesis is a multistep process involving repeated selection and clonal expansion of cells that acquire the ability to proliferate and function uncontrollably as a result of genetic mutations. Increased activation of Rho GTPases, a subfamily of the Ras superfamily of small G-proteins, has been shown to confer cells with certain growth properties characteristic of malignant cells. However, the specific contribution of Rho GTPases to the malignant transformation of human fibroblasts has not been determined. My research emphasis has been to investigate the role of two members of the Rho subfamily, Cdc42 and Rac1, in the malignant transformation of human fibroblasts. Cdc42 and Rac1 were studied in parallel because they often act in the same pathways to regulate transcription of genes, cell cycle progression, cell differentiation, survival and apoptosis pathways, and membrane trafficking. For my studies, I chose two tumor-derived cell lines generated from the human fibroblast MSU1 cell lineage that display increased Cdc42 and Rac1 activity.
520 $a To investigate whether Cdc42 and Rac1 act as downstream mediators of oncogenic H-RAS, dominant-negative Cdc42 and/or Rac1 mutants were expressed in cells malignantly transformed by oncogenic H-RAS. Expression of dominant-negative mutant(s) in these cells significantly inhibited growth properties characteristic of the parental cell line, such as rapid cellular proliferation, focus-forming ability in culture, and tumor formation in athymic mice. These results indicate that intact Cdc42 and Rac1 activity are required for oncogenic H-RAS transformation of human fibroblasts. Affymetrix GeneChip analysis was carried out to identify genes regulated by expression of oncogenic H-RAS <italic>and</italic> dominant-negative Cdc42 and Rac1 mutants. The mRNA expression of 28 genes was regulated in this manner. The endothelial PAS domain 1 (EPAS1) gene encodes a hypoxia-induced transcription factor and is one of nine genes that were dependent on intact Cdc42 and Rac1 activity for up-regulation by oncogenic H-RAS. Further analysis showed that secretion of vascular endothelial growth factor, a gene known to be up-regulated by EPAS1, was dependent upon Cdc42 and Rac1 activity.
520 $a To investigate the importance of endogenous, hyperactive Cdc42 and Rac1 in maintenance of growth properties characteristic of malignant cells, dominant-negative Cdc42 and/or Rac1 mutants were expressed in carcinogen-transformed cells that display a high level of Cdc42 and Rac1 activity. The activity of Cdc42 and Rac1 were determined by a p21-activated kinase pull-down assay, which utilizes the fact that the p21-binding domain only binds to activated, GTP-bound forms of Cdc42 and Rac1. The cells were infected with retroviruses carrying the cDNA encoding β-galactosidase, dominant-negative Cdc42, dominant-negative Rac1, or both mutants, and then selected with puromycin for the drug resistance marker. Three independent cell populations were generated for each cDNA, and the cells were injected subcutaneously into athymic mice. In addition, clonally-derived cell populations that express either a low or high level of the mutant(s) were established, as a more definitive test of the effect of dominant-negative mutant(s) expression on tumor formation in athymic mice.
590 $a School code: 0128.
650 4 $a Biology, Cell. $3 1017686
650 4 $a Biology, Genetics. $3 1017730
650 4 $a Biology, Molecular. $3 1017719
690 $a 0307
690 $a 0369
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710 2 0 $a Michigan State University. $3 676168
773 0 $t Dissertation Abstracts International $g 63-09B.
790 $a 0128
790 1 0 $a McCormick, J. Justin, $e advisor
791 $a Ph.D.
792 $a 2002
856 4 0 $u http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3064216