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The oncogenic transcription factor IRF-2 possesses a transcriptional repression and a latent activation domain
H Yamamoto1, M S Lamphier, T Fujita
1Institute for Molecular and Cellular Biology, Osaka University, Japan.
Abstract:
IRF-1 and IRF-2 are two structurally related transcription factors originally identified as regulators of the type I interferon (IFN) system. IRF-1 functions as an activator whereas IRF-2 binds to the same cis-elements and can repress IRF-1 action. More recently these two factors have been shown to act in a mutually antagonistic manner to regulate cell growth; overexpression of the repressor IRF-2 leads to cell transformation, whereas concomitant overexpression of IRF-1 leads to reversion. Previous studies have identified DNA-binding domains in IRF-1 and IRF-2 and an activation domain in IRF-1. In the present study we show that IRF-2 also possesses a transcriptional repression domain in its carboxyl terminal region. We further observe that a LexA-IRF2 fusion can inhibit the function of an activator positioned nearby in the promoter. Thus, repression by IRF-2 may involve both competition with IRF-1 for binding to the promoter as well as the 'silencing' of nearby activators. Furthermore, we demonstrate the presence of a latent activation domain in the central region of IRF-2 and speculate that IRF-2 may contribute to gene activation under certain conditions.
Insights
Interferon regulatory factors (IRFs) control cell growth. This study reveals Interferon regulatory factor-2 (IRF-2) has a repression domain, explaining its role in cell transformation and potential gene activation.
Area of Science:
- Molecular Biology
- Genetics
- Cell Biology
Background:
- Interferon regulatory factors (IRFs) are transcription factors crucial for the type I interferon (IFN) system.
- IRF-1 acts as an activator, while IRF-2 acts as a repressor, binding to similar DNA elements.
- IRF-1 and IRF-2 antagonistically regulate cell growth, with IRF-2 overexpression linked to transformation and IRF-1 to reversion.
Purpose of the Study:
- To investigate the functional domains of IRF-2 beyond its known DNA-binding capacity.
- To elucidate the mechanisms by which IRF-2 represses gene transcription.
- To explore the potential for IRF-2 to also exhibit gene activation properties.
Main Methods:
- Analysis of IRF-2's carboxyl-terminal region to identify functional domains.
- Construction and testing of a LexA-IRF2 fusion protein to assess its effect on promoter activity.
- Biochemical and genetic assays to characterize IRF-2's interaction with DNA and other regulatory proteins.
Main Results:
- IRF-2 possesses a transcriptional repression domain in its carboxyl-terminal region.
- A LexA-IRF2 fusion protein demonstrated the ability to inhibit nearby transcriptional activators.
- Evidence suggests IRF-2 can repress gene expression through promoter binding competition and active silencing.
- A latent activation domain was identified in the central region of IRF-2.
Conclusions:
- IRF-2's repressive function is mediated by its carboxyl-terminal domain, potentially through multiple mechanisms.
- IRF-2's role in cell growth regulation is complex, involving both repression and potentially activation under specific circumstances.
- These findings deepen the understanding of IRF family functions in gene regulation and cellular processes.