Cooperative regulation of the interferon regulatory factor-1 tumor suppressor protein by core components of the molecular chaperone machinery

Vikram Narayan, Mirjam Eckert, Alicja Zylicz, Maciej Zylicz, Kathryn L> Ball

    Research output: Contribution to journalArticle

    16 Citations (Scopus)

    Abstract

    Our understanding of the post-translational processes involved in regulating the interferon regulatory factor-1 (IRF-1) tumor suppressor protein is limited. The introduction of mutations within the C-terminal Mf1 domain (amino acids 301-325) impacts on IRF-1-mediated gene repression and growth suppression as well as the rate of IRF-1 degradation. However, nothing is known about the proteins that interact with this region to modulate IRF-1 function. A biochemical screen for Mf1-interacting proteins has identified an LXXLL motif that is required for binding of Hsp70 family members and cooperation with Hsp90 to regulate IRF-1 turnover and activity. These conclusions are supported by the finding that Hsp90 inhibitors suppress IRF-1-dependent transcription shortly after treatment, although at later time points inhibition of Hsp90 leads to an Hsp70-dependent depletion of nuclear IRF-1. Conversely, the half-life of IRF-1 is increased by Hsp90 in an ATPase-dependent manner leading to the accumulation of nuclear but not cytoplasmic IRF-1. This study begins to elucidate the role of the Mf1 domain of IRF-1 in orchestrating the recruitment of regulatory factors that can impact on both its turnover and transcriptional activity.
    Original languageEnglish
    Pages (from-to)25889-25899
    Number of pages11
    JournalJournal of Biological Chemistry
    Volume284
    Issue number38
    DOIs
    Publication statusPublished - 18 Sep 2009

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