عنوان

The role of Rho proteins in transformation by G protein-coupled receptors

Number

TLpq304458393

.Language of Text, Soundtrack etc

انگلیسی

Title Proper

The role of Rho proteins in transformation by G protein-coupled receptors

General Material Designation

[Thesis]

First Statement of Responsibility

I. E. Zohn

Subsequent Statement of Responsibility

C. J. Der

Name of Publisher, Distributor, etc.

The University of North Carolina at Chapel Hill

Date of Publication, Distribution, etc.

1998

Specific Material Designation and Extent of Item

140

Dissertation or thesis details and type of degree

Ph.D.

Body granting the degree

The University of North Carolina at Chapel Hill

Text preceding or following the note

1998

Text of Note

G protein-coupled receptors transduce extracellular signals from a wide variety of ligands to regulate a broad range of physiological responses. This family of cell surface receptors share a conserved predicted tertiary structure consisting of seven membrane spanning domains flanked by extracellular and intracellular loops. Upon ligand binding, G protein-coupled receptors activate heterotrimeric GTP-binding proteins (G-proteins) which regulate a variety of signal transduction pathways. The isolation of the mas oncogene provided the first indication that G protein-coupled receptors could behave as oncogenes. Since the isolation of Mas, a number of other G protein-coupled receptors and Gusd\alphausd-subunits have been shown to cause transformation of rodent fibroblasts. Additionally, G protein coupled receptors may also be involved in human tumor formation. The overall goal of my dissertation studies was to determine the mechanism of transformation by G protein-coupled receptors. G protein coupled receptors can activate a number of signal transduction pathways which may contribute to transformation. Both transforming G protein-coupled receptors and Gusd\alphausd subunits have been shown to activate Ras and Rho-dependent signal transduction pathways, and Ras and Rho proteins are involved in transformation by a number of different oncogenes. However, a role for activation of Ras and Rho in transformation by G protein-coupled receptor oncogenes was not demonstrated. We used three different transforming G protein-coupled receptors to investigate the mechanism of transformation of NIH 3T3 cells by G protein-coupled receptors: the mas oncogene, XGR and a turkey P2Y-purinergic receptor. Results from these studies suggest that activation of Rho family proteins is an essential mechanism of transformation by G protein-coupled receptors. Furthermore, these transforming G protein-coupled receptors exhibited two different mechanisms of transformation. Mas and the P2Y-purinergic receptor caused transformation by a Rac1-like mechanism, whereas XGR caused transformation by a RhoA-like mechanism. Finally, evidence is presented that the turkey P2Y-purinergic receptor and the mas oncogene cause transformation by coordinate activation of usd\rm G\alpha\sb{i}usd and usd\rm G\alpha\sb{q},usd whereas XGR causes transformation by activation of usd\rm G\alpha\sb.usd These results suggest that Rho proteins maybe an effective anti-cancer drug target for tumors which have up regulated activity of G protein-coupled receptors.

Biological sciences

G protein-coupled receptors

Pure sciences

Rho proteins

Signal transduction

Transformation

C. J. Der

I. E. Zohn

Electronic name

p

[Thesis]

276903

a

Y