Eukaryotic transcriptional regulatory complexes: cooperativity from near and afar

https://doi.org/10.1016/S0959-440X(03)00012-5Get rights and content

Abstract

It is characteristic of eukaryotic transcription that a unique combination of multiple transcriptional regulatory proteins bound to promoter DNA specifically activate or repress downstream target genes; this is referred to as combinatorial gene regulation. Recently determined structures have revealed different modes of protein–protein interaction on the promoter DNA from near (e.g. the Runx1–CBFβ–DNA, NFAT–Fos–Jun–DNA, GABPα–GABPβ–DNA, Ets-1–Pax-5–DNA and PU.1–IRF-4–DNA complexes) and afar with DNA looping (e.g. the c-Myb–C/EBPβ–DNA complex), and their regulatory mechanisms.

Introduction

Precise transcriptional control is essential to the biological activities of eukaryotic multicellular organisms, including cell growth and differentiation, homeostasis, immunological events and so on. Generally, eukaryotic transcriptional regulation is conducted synergistically by multiple transcriptional regulatory factors, which bind to the promoter DNA 1., 2., 3.. The involvement of different kinds of transcription factors in gene regulation makes possible the integration of several signaling pathways in the nucleus. The interactions between transcriptional regulatory factors on promoter DNA that underlie this so-called ‘combinatorial transcriptional regulation’ can be classified into three modes: those between a DNA-binding factor and a non-DNA-binding factor; those between DNA-binding factors adjacently located on the promoter; and those between DNA-binding factors separately or distantly located on the promoter (Figure 1). To date, various crystallographic structures of eukaryotic multiple transcriptional regulatory factor–DNA complexes exhibiting the first and second modes, and one structure exhibiting the third mode have appeared. With an emphasis on the Runx1–CBFβ–DNA and c-Myb–C/EBPβ–DNA complexes, we discuss here the regulatory mechanisms for modulating the DNA-binding activity and for constructing the stereospecific protein assembly on the promoter DNA.

Section snippets

The allosteric modulation of Runx1–DNA binding by CBFβ

The eukaryotic transcriptional regulatory factors Runx1 (Runt-related protein 1) and CBFβ (core-binding factor β) play essential roles in hematopoiesis in the fetal liver, in the emergence of definitive hematopoietic cells from hemogenic endothelia in the developing embryo and in angiogenesis. The genes encoding these proteins are frequently targeted by chromosomal translocation, inversion and point mutations in acute myeloid and lymphoid leukemias, blast crises in chronic myeloid leukemia,

A common aspect of DNA-binding regulation in the Runx1–CBFβ–DNA complex and other multiprotein–DNA complexes

To date, a few eukaryotic heteromultimeric protein–DNA complexes have been analyzed at atomic level. To examine whether the elucidated regulatory mechanism for Runx1 is also true for other interactions between transcription factors on promoter DNA, a complex structure comprising NFAT1 (nuclear factor of activated T cells 1), which has a pair of Ig-like fold domains, the Fos–Jun heterodimer and the IL-2 (interleukin-2) gene promoter DNA [8] was compared with the structure of the Runx1–CBFβ–DNA

Synergism between proteins separately or distantly bound to DNA

In eukaryotes, various kinds of transcriptional regulatory factors bind to a wide promoter DNA region to synergistically regulate the transcription of target genes. To explain the possible mechanisms for this trans-activational synergy, a stereospecific multiprotein assembly on the promoter DNA, which induces or stabilizes DNA looping, has been proposed as the most accepted model; this model is referred to as the enhanceosome 1., 2., although other mechanisms have also been proposed, including

A cooperative interaction between c-Myb and C/EBPβ separately bound to a promoter

The c-Myb transcriptional regulator is involved in the proliferation and differentiation of hematopoietic cells. Specifically, it cooperates with a C/EBP (CAAT/enhancer-binding protein) family member to induce myeloid cell differentiation. c-Myb has three tandem subdomains (R1, R2 and R3), each bearing an HTH-related motif, in its DNA-binding domain 18., 19., 20., whereas C/EBP family members contain a bZip-type motif for DNA binding. The mim-1 promoter is a well-characterized c-Myb target gene

DNA looping induced by prokaryotic and eukaryotic transcriptional regulatory factors

The mechanisms of DNA loop formation have been studied theoretically and experimentally 13., 14., 22.. A simple simulation of the formation of a DNA loop by the interaction of two proteins separately bound to DNA cannot explain the formation of a relatively small DNA loop with an intervening sequence of less than 200 base pairs, such as the mim-1 promoter loop induced by c-Myb and C/EBPβ. However, in general, the ‘upstream elements’ to which multiple transcriptional regulatory factors bind are

Conclusions

In transcriptional regulation, two factors are considered to be involved: stabilization of the regulatory factor–DNA complex, and formation of the stereospecific assembly of these proteins on the looped or deformed DNA. For stabilization of the protein–DNA interactions, a direction-sensitive protein backbone amide–DNA phosphate hydrogen bond, whose formation depends on the protein conformation and which is surrounded by interactions of the sidechains of adjacent residues with DNA minor groove

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

The authors thank Shunsuke Ishii for helpful discussions and Masaaki Shiina for help preparing the figures. The authors also thank Scott A Ness for providing the mim-1 promoter construct.

References (45)

  • L. Ringrose et al.

    Quantitative comparison of DNA looping in vitro and in vivo: chromatin increases effective DNA flexibility at short distances

    EMBO J.

    (1999)
  • H.S. Koo et al.

    DNA bending at adenine thymine tracts

    Nature

    (1986)
  • B. Revet et al.

    Four dimers of lambda repressor bound to two suitably spaced pairs of lambda operators form octamers and DNA loops over large distances

    Curr. Biol.

    (1999)
  • W. Su et al.

    DNA-looping and enhancer activity: association between DNA-bound NtrC activator and RNA polymerase at the bacterial glnA promoter

    Proc. Natl. Acad. Sci. USA

    (1990)
  • I.A. Mastrangelo et al.

    DNA looping and Sp1 multimer links: a mechanism for transcriptional synergism and enhancement

    Proc. Natl. Acad. Sci. USA

    (1991)
  • P. Jackson et al.

    Synergistic transcriptional activation of the MCK promoter by p53: tetramers link separated DNA response elements by DNA looping

    Oncogene

    (1998)
  • S.M. Soisson et al.

    Structural basis for ligand-regulated oligomerization of AraC

    Science

    (1997)
  • C. Wolberger

    Multiprotein-DNA complexes in transcriptional regulation

    Annu. Rev. Biophys. Biomol. Struct.

    (1999)
  • J. Bravo et al.

    The leukemia-associated AML1 (Runx1)-CBFβ complex functions as a DNA-induced molecular clamp

    Nat. Struct. Biol.

    (2001)
  • S. Backstrom et al.

    The RUNX1 Runt domain at 1.25Å resolution: a structural switch and specifically bound chloride ions modulate DNA binding

    J. Mol. Biol.

    (2002)
  • D. Bartfeld et al.

    DNA recognition by the RUNX1 transcription factor is mediated by an allosteric transition in the RUNT domain and by DNA bending

    Structure

    (2002)
  • C.W. Garvie et al.

    Structural studies of Ets-1/Pax5 complex formation on DNA

    Mol. Cell

    (2001)
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