The role of phospholipase D in human cancer cells with activated Ras.
Item
-
Title
-
The role of phospholipase D in human cancer cells with activated Ras.
-
Identifier
-
AAI3296925
-
identifier
-
3296925
-
Creator
-
Shi, Ming.
-
Contributor
-
Adviser: David A. Foster
-
Date
-
2008
-
Language
-
English
-
Publisher
-
City University of New York.
-
Subject
-
Biology, Molecular
-
Abstract
-
Phospholipase D (PLD) is a ubiquitous enzyme which hydrolyzes phosphatidylcholine to phosphatidic acid and choline. PLD can be activated by various factors and plays a vital role in cell transformation, survival and other cellular processes. Activating Ras mutations are common in many human cancers and have been found to play important roles in cell proliferation and survival. In this dissertation we establish a role for PLD in the survival of human cancer cells with activating mutations in both H-Ras and K-Ras.;T24 bladder carcinoma cells express an activated H-Ras gene and Calu-1 lung carcinoma cells express an activated K-Ras gene. We found that both of these cancer cell lines have highly elevated levels of PLD activity and that the PLD activity is dependent on Ras. The PLD activity was also dependent on two downstream targets of Ras signaling RalA and phosphatidylinositol-3-kinase. Suppression of Ras, RalA and phosphatidylinositol-3-kinase resulted in apoptosis in the absence of serum. Suppression of PLD activity in the T24 and Calu-1 cells resulted in apoptotic cell death in the absence of serum, indicating that the elevated PLD activity provides a survival signal in these cancer cell lines. These data indicate that a critical component of Ras signaling in human cancer cells is the activation of PLD.;We also examined the effects of H-Ras and K-Ras in 3Y1 rat fibroblasts. We found that H-Ras reduced cell viability whereas K-Ras did not. These data suggest a rationale for the high frequency of K-Ras mutation in human cancers relative to H-Ras because human cancers with activated H-Ras are more likely to undergo apoptosis unless a survival signal is provided to prevent this from taking place.;Collectively, the studies described in this dissertation suggest that targeting PLD survival signals in cancer cells could be an effective strategy to induce apoptosis in human cancer cells with activated Ras.
-
Type
-
dissertation
-
Source
-
PQT Legacy CUNY.xlsx
-
degree
-
Ph.D.
