Novel functions of the phosphatidylinositol metabolic pathway discovered by a chemical genomics screen with wortmannin

 
Proc Natl Acad Sci U S A 2003 Mar 18;100(6):3345-50  

 

 
Novel functions of the phosphatidylinositol metabolic pathway discovered by a chemical genomics screen with wortmannin.

Zewail A, Xie MW, Xing Y, Lin L, Zhang PF, Zou W, Saxe JP, Huang J.

Department of Molecular and Medical Pharmacology, Molecular Biology Institute, and University of California Los Angeles-Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095.

We report a novel connection between the phosphatidylinositol (PI) metabolic pathway and the DNA replication and damage checkpoint pathway discovered from an unbiased chemical genomics screen. Substrates and products of PI kinases are important signaling molecules that affect a wide range of biological processes. The full collection of yeast deletion strains was screened to identify genes that confer altered sensitivity to the natural product wortmannin, a PI kinase inhibitor. These experiments have allowed us to explore metabolomic and proteomic implications of PI synthesis and turnover. This study also uncovers other biological processes affected by wortmannin treatment, including proteasome-mediated degradation and chromatin remodeling. Bioinformatic analyses were used to reveal the relative distances among cellular processes affected by wortmannin and protein-protein interactions in the wortmannin-sensitive proteomic subnetwork. These results illustrate the great utility of using a whole-genome approach in annotating the biological effects of small molecules and have clear implications for pharmacogenomics. Furthermore, our discovery points to a route to overcoming genome instability, a result of defective DNA damage signalingrepair and a hallmark of cancer.

PMID: 12615994
 

 

 

 

 

 


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