Antisense DNAs as multisite genomic modulators identified by DNA microarray

Yee Sook Cho, Meyoung-Kon Kim, Chris Cheadle, Catherine Neary, Kevin G. Becker, Yoon S. Cho-Chung

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Antisense oligodeoxynucleotides can selectively block disease-causing genes, and cancer genes have been chosen as potential targets for antisense drugs to treat cancer. However, nonspecific side effects have clouded the true antisense mechanism of action and hampered clinical development of antisense therapeutics. Using DNA microarrays, we have conducted a systematic characterization of gene expression in cells exposed to antisense, either exogenously or endogenously. Here, we show that in a sequence-specific manner, antisense targeted to protein kinase A RIα alters expression of the clusters of coordinately expressed genes at a specific stage of cell growth, differentiation, and activation. The genes that define the proliferation-transformation signature are down-regulated, whereas those that define the differentiation-reverse transformation signature are up-regulated in antisense-treated cancer cells and tumors, but not in host livers. In this differentiation signature, the genes showing the highest induction include genes for the G proteins Rap1 and Cdc42. The expression signature induced by the exogenously supplied antisense oligodeoxynucleotide overlaps strikingly with that induced by endogenous antisense gene overexpression. Defining antisense DNAs on the basis of their effects on global gene expression can lead to identification of clinically relevant antisense therapeutics and can identify which molecular and cellular events might be important in complex biological processes, such as cell growth and differentiation.

Original languageEnglish
Pages (from-to)9819-9823
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number17
DOIs
Publication statusPublished - 2001 Aug 14
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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