A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors.

Douarin, Bertrand Le; Nielsen, Anders Lade; Garnier, J M; Ichinose, Hiroshi; Jeanmougin, F; Losson, Régine; Chambon, Pierre

doi:10.1002/j.1460-2075.1996.tb01060.x

Cited by 505 publications

(541 citation statements)

References 93 publications

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“…In animals, this short L**LL motif exists in a large variety of nuclear proteins functioning as transcriptional coactivators, such as SRC-1/p160, TIF-2/GRIP-1, CBP/p300, and RIP-140. The animal L**LL motif mediates binding to liganded nuclear receptors and other transcription factors, such as the cAMP response element-binding (CREB) protein, which is one of the best characterized bZIP proteins in animals (Ribeiro et al, 1994;Le Douarin et al, 1996;Heery et al, 1997;Voegel et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…2A). This peptide resembles the a-helical L**LL motif known to mediate the interaction between transcriptional coactivators and liganded nuclear receptors as well as many other transcription factors in animals through a hydrophobic face formed by its Leu residues (Le Douarin et al, 1996;Heery et al, 1997;Voegel et al, 1998). To test by yeast twohybrid interaction screens whether this a-helical L**LL motif of ROXY1 is essential for binding to plant TGA transcription factors, five mutagenized ROXY1 proteins were engineered by replacing one, two, or all three strongly hydrophobic Leu residues located in this motif by an Ala, which possesses a shorter and thus only weakly hydrophobic side chain ( Fig.…”

Section: Analysis Of the Roxy1 C-terminal L**ll Motifmentioning

confidence: 99%

“…This L**LL motif is shown to be essential for an interaction with TGA transcriptional factors and is indispensable for Arabidopsis petal development. Similar to the a-helical L**LL motifs of transcriptional coactivators that interact with liganded nuclear receptors as well as many other transcription factors in animals (Le Douarin et al, 1996;Heery et al, 1997;Voegel et al, 1998), a hydrophobic face formed by the conserved Leu residues in the L**LL motif of ROXY1 likely mediates the interaction with TGA transcription factors. Although crucial Cys residues of TGA proteins were identified as potential targets to be posttranslationally modified by ROXYs (Després et al, 2003;Murmu et al, 2010), little is known about the TGA domains mediating the interaction with ROXYs.…”

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The ROXY1 C-Terminal L**LL Motif Is Essential for the Interaction with TGA Transcription Factors

Gutsche

Zachgo

2011

Plant Physiology

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Glutaredoxins (GRXs) are small, ubiquitous, glutathione-dependent oxidoreductases that participate in redox-regulated processes associated with stress responses. Recently, GRXs have been shown to exert crucial functions during flower developmental processes. GRXs modulate their target protein activities by the reduction of protein disulfide bonds or deglutathionylation reactions. The Arabidopsis (Arabidopsis thaliana) GRX ROXY1 participates in petal primordia initiation and further petal morphogenesis. ROXY1 belongs to a land plant-specific class of GRXs with a CC-type active site motif, deviating from the ubiquitously occurring CPYC and CGFS GRX classes. ROXY1 was previously shown to interact with floral TGA transcription factors in the nucleus, and this interaction is a prerequisite for ROXY1 to exert its activity required for Arabidopsis petal development. Deletion analysis further identified the importance of the ROXY1 C terminus for the ROXY1/ TGA protein interactions and for the ROXY1 function in petal development. Here, by dissecting the ROXY1 C terminus, an a-helical L**LL motif immediately adjacent to the ROXY1 C-terminal eight amino acids was identified that is essential for the interaction with TGA transcription factors and crucial for the ROXY1 function in planta. Similar to the a-helical L**LL motifs binding to transcriptional coactivators with liganded nuclear receptors in animals, a hydrophobic face formed by the conserved leucines in the L**LL motif of ROXY1 possibly mediates the interaction with TGA transcription factors. Thus, the a-helical L**LL sequence is a conserved protein-protein interaction motif in both animals and plants. Furthermore, two separate TGA domains were identified by deletion experiments as being essential for mediating TGA protein interactions with ROXYs.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of the Roxy1 C-terminal L**ll Motifmentioning

confidence: 99%

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confidence: 99%

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The ROXY1 C-Terminal L**LL Motif Is Essential for the Interaction with TGA Transcription Factors

Gutsche

Zachgo

2011

Plant Physiology

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“…We show that the PHD finger and the bromodomain of KAP1 function interdependently in catalyzing SUMOylation of lysine residues within this tandem module. Our new structural and mechanistic insights into the molecular function of the tandem PHD finger-bromodomain provide a framework for the functional understanding of KAP1 as the co-repressor for the Kruppel-associated box (KRAB) C2H2 zinc-finger family of proteins, many of which are involved in the regulation of cell differentiation and development [34][35][36] . …”

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confidence: 99%

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Zeng

Yap

Ivanov

et al. 2008

Nat Struct Mol Biol

117

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The tandem PHD finger-bromodomain, found in many chromatin-associated proteins, has an important role in gene silencing by the human co-repressor KRAB-associated protein 1 (KAP1). Here we report the three-dimensional solution structure of the tandem PHD finger-bromodomain of KAP1. The structure reveals a distinct scaffold unifying the two protein modules, in which the first helix, α Z , of an atypical bromodomain forms the central hydrophobic core that anchors the other three helices of the bromodomain on one side and the zinc binding PHD finger on the other. A comprehensive mutation-based structure-function analysis correlating transcriptional repression, ubiquitin-conjugating enzyme 9 (UBC9) binding and SUMOylation shows that the PHD finger and the bromodomain of KAP1 cooperate as one functional unit to facilitate lysine SUMOylation, which is required for KAP1 co-repressor activity in gene silencing. These results demonstrate a previously unknown unified function for the tandem PHD finger-bromodomain as an intramolecular small ubiquitin-like modifier (SUMO) E3 ligase for transcriptional silencing.Chemical modifications of chromatin on the DNA (for example, methylation of cytosine) and DNA-packing histones (for example, acetylation, methylation, phosphorylation, ubiquitination and SUMOylation) are important in the epigenetic control of gene transcription in response to physiological and environmental stimuli [1][2][3] . An emerging model suggests that there is an 'epigenetic code' embedded within chromatin to signify regions of distinct nuclear activities, such as heterochromatin formation or transcriptional activation [4][5][6] . It is thought that the epigenetic code is established by chromatin-modifying enzymes and interpreted by proteins that bind the chromatin in a modification-sensitive manner. The discovery of methyl-CpG binding domains 7 , bromodomains as acetyllysine binding The tandem bromodomain-PHD finger of the human transcriptional coactivator p300/CBP has been shown to be interdependent in interactions with nucleosomes 27 . A more common, reversely connected motif, the PHD finger-bromodomain, is found in many chromatinassociated proteins including histone lysine methyl-transferase MLL1 (ref. 28), Williams syndrome transcription factor (WSTF) in the chromatin-remodeling complex WINAC 29 , and the TIF1 family proteins (α, β, γ and δ; note that TIF1β is also known as KAP1 or TRIM28) 30 . This tandem PHD finger-bromodomain is also found in Sp140, a leukocytespecific protein in the nuclear body that is involved in the pathogenesis of acute promyelocytic leukemia and viral infection 31 . Mutations of PHD fingers, particularly those that disrupt zinc coordination, have been linked to tumor formation and genetic disorders 32 .More recently, it has been reported that the PHD finger of the human co-repressor KAP1 functions as a unique SUMO E3 ligase that is required for KAP1's gene transcription repression activity 33 .To understand its molecular function in gene silencing, we solved the three-dim...

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“…When bound to DNA by a specific DBD, the KRAB domain binds to the corepressor KAP-1, which suppresses transcription by either directly inhibiting the transcriptional machinery and/or by altering the chromatin structure (Friedman et al, 1996;Le Douarin et al, 1996;Moosmann et al, 1996;Darnell and Richardson, 1999). Indeed, KRAB/FLI-1 inhibited EWS/FLI-1 transformation in our study.…”

Section: Discussionmentioning

confidence: 99%

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

Chan

Wilson

et al. 2003

Br J Cancer

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Ewing's sarcoma is a childhood bone tumour with poor prognosis, most commonly associated with a t(11;22)(q24;q12) reciprocal translocation that fuses the EWS and FLI-1 genes, resulting in the production of an aberrant chimeric transcription factor EWS/FLI-1. To elucidate the mechanisms by which EWS/FLI-1 mediates transformation in mouse models, we have generated a murine Ews/Fli-1 fusion protein. We demonstrate that this protein transforms fibroblast cells in vitro similar to human EWS/FLI-1 as demonstrated by serum and anchorage-independent growth, the formation of tumours in nude mice and elevation of the oncogenic marker c-myc. Furthermore, transformation of these cells was inhibited by a specific repressor, KRAB/FLI-1. The KRAB/FLI-1 repressor also suppressed the tumorigenic phenotype of a human Ewing's sarcoma cell line. These findings suggest that the transformed phenotype of Ewing's sarcoma cells can be reversed by using the sequence-specific FLI-1-DNA-binding domain to target a gene repressor domain. The inhibition of EWS/FLI-1 is the first demonstration of the KRAB domain suppressing the action of an ETS factor. This approach provides potential avenues for the elucidation of the biological mechanisms of EWS/FLI-1 oncogenesis and the development of novel therapeutic strategies.

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A possible involvement of TIF1 alpha and TIF1 beta in the epigenetic control of transcription by nuclear receptors.

Cited by 505 publications

References 93 publications

The ROXY1 C-Terminal L**LL Motif Is Essential for the Interaction with TGA Transcription Factors

The ROXY1 C-Terminal L**LL Motif Is Essential for the Interaction with TGA Transcription Factors

Structural insights into human KAP1 PHD finger–bromodomain and its role in gene silencing

Transformation induced by Ewing's sarcoma associated EWS/FLI-1 is suppressed by KRAB/FLI-1

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