Targeting protein inactivation through an oligomerization chain reaction

Francesco Contegno, Mario Cioce, Pier Giuseppe Pelicci, Saverio Minucci

Research output: Contribution to journalArticlepeer-review

Abstract

A general strategy for inactivation of target proteins is presented, which we have termed "oligomerization chain reaction." This technique is based on the fusion of the self-associating coiled-coil (CC) domain of the nuclear factor promyelocytic leukemia (PML) to target proteins that are able to self-associate naturally. Oligomerization through the CC region of promyelocytic leukemia, and through the natural self-associating domain, triggers the oligomerization chain reaction, leading to formation of large molecular weight complexes and functional inactivation of the target. As a test case, we have chosen the oncosuppressor p53, naturally occurring as a tetramer. Fusion of the CC to p53 leads to formation of stable high molecular weight complexes - as shown by size exclusion chromatography - to which wild-type p53 is recruited with high efficiency. CC-p53 chimeras delocalize wild-type p53 to the cytoplasm and inhibit its transcriptional regulatory properties, resulting in a loss of p53 function. We propose that this strategy may be of general application to self-associating factors and represent a complementary approach to currently used functional inactivation-based strategies.

Original languageEnglish
Pages (from-to)1865-1869
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume99
Issue number4
DOIs
Publication statusPublished - Feb 19 2002

ASJC Scopus subject areas

  • General
  • Genetics

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