An artificial cell-cycle inhibitor isolated from a combinatorial library

Barak A. Cohen, Pierre Colas, Roger Brent

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

Understanding the genetic networks that operate inside cells will require the dissection of interactions among network members. Here we describe a peptide aptamer isolated from a combinatorial library that distinguishes among such interactions. This aptamer binds to cyclin-dependent kinase 2 (Cdk2) and inhibits its kinase activity. In contrast to naturally occurring inhibitors, such as p21(Cip1), which inhibit the activity of Cdk2 on all its substrates, inhibition by pep8 has distinct substrate specificity. We show that the aptamer binds to Cdk2 at or near its active site and that its mode of inhibition is competitive. Expression of pep8 in human cells retards their progression through the G1 phase of the cell cycle. Our results suggest that the aptamer inhibits cell-cycle progression by blocking the activity of Cdk2 on substrates needed for- the G1-to-S transition. This work demonstrates the feasibility of selection of artificial proteins to perform functions not developed during evolution. The ability to select proteins that block interactions between a gene product and some partners but not others should make sophisticated genetic manipulations possible in human cells and other currently intractable systems.

Original languageEnglish
Pages (from-to)14272-14277
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume95
Issue number24
DOIs
StatePublished - Nov 24 1998
Externally publishedYes

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