Distamycin-induced inhibition of homeodomain-DNA complexes.

Dorn, Arnulf; Affolter, Markus; Müller, Martin; Gehring, W.J.; Leupin, Werner

doi:10.1002/j.1460-2075.1992.tb05050.x

Cited by 87 publications

(61 citation statements)

References 77 publications

(91 reference statements)

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“…A similar model has been suggested to explain the effect of distamycin A on the Antennapedia HD⅐DNA complex (52). Interestingly, it has already been proposed that distamycin A and HMGI DNA binding domains have a similar planar crescent-shaped structure and can compete for the binding in the minor groove of AT-rich sequences (16).…”

Section: Fig 4 Kinetics Of Hmgi-c Inhibitory Effect On Hd-cant1 Intmentioning

confidence: 56%

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High Mobility Group I Proteins Interfere with the Homeodomains Binding to DNA

Arlotta

Rustighi

Mantovani

et al. 1997

Journal of Biological Chemistry

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Homeodomains (HDs) constitute the DNA binding domain of several transcription factors that control cell differentiation and development in a wide variety of organisms. Most HDs recognize sequences that contain a 5-TAAT-3 core motif. However, the DNA binding specificity of HD-containing proteins does not solely determine their biological effects, and other molecular mechanisms should be responsible for their ultimate functional activity. Interference by other factors in the HD/DNA interaction could be one of the processes by which HD-containing proteins achieve the functional complexity required for their effects on the expression of target genes.Using gel-retardation assay, we demonstrate that two members of the high mobility group I (HMGI) family of nuclear proteins (HMGI-C and HMGY) can bind to a subset of HD target sequences and inhibit HDs from binding to the same sequences. The inhibition of the HD/DNA interaction occurs while incubating HMGI-C with DNA either before or after the addition of the HD.The reduced half-life of the HD⅐DNA complex in the presence of HMGI-C, and the shift observed in the CD spectra recorded upon HMGI-C binding to DNA, strongly suggest that structural modifications of the DNA are responsible for the inhibition of the HD⅐DNA complex formation. Moreover, by co-transfection experiments we provide evidence that this inhibition can occur also in vivo.The data reported here would suggest that HMGI proteins may be potential regulators of the function of HDcontaining proteins and that they are able to interfere with the access of the HD to their target genes. Homeodomains (HDs)1 are 61-amino acid-long structures that are able to interact with DNA in a sequence-specific manner (1). They represent the DNA binding domain of a large number of transcription factors that control cell fate decisions in a wide range of organisms, including yeast, insects, and vertebrates (2, 3). The structure of HDs and their mode of DNA interaction are conserved (1,4,5). With a few exceptions, sequences recognized by HDs possess a 5Ј-TAAT-3Ј core motif (6 -8). Though recognizing similar DNA sequences, when expressed in the same temporal and spatial context, distinct HD-containing proteins may show different biological activities (9, 10). These findings indicate that the DNA binding specificity of these proteins cannot be the only molecular event that determines their biological effect. In fact, some other molecular mechanisms have been identified, in addition to the DNA binding specificity, that allow the selection of different target genes by distinct HD-containing proteins (11,12). One of these mechanisms is based on the differential interaction of HD-containing proteins with accessory factors that mediate the contacts with the basal transcriptional machinery. For example, the Pou-domain-containing proteins Oct-1 and Oct-2 bind to the same DNA sequence, yet only the former is able to interact with the acidic transcriptional activator VP16 (11). Another mechanism is based on specific protein-protein interactions...

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Section: Fig 4 Kinetics Of Hmgi-c Inhibitory Effect On Hd-cant1 Intmentioning

confidence: 56%

“…Moreover, it has been demonstrated that, even at very high concentrations, this drug is not able to affect HDs/DNA interactions (52). Therefore, berenil should compete with HMGI-C for the minor groove interaction and reduce the inhibitory effect of this protein on HD binding to DNA.…”

Section: Hmgi Proteinsmentioning

confidence: 99%

High Mobility Group I Proteins Interfere with the Homeodomains Binding to DNA

Arlotta

Rustighi

Mantovani

et al. 1997

Journal of Biological Chemistry

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“…For example, the A͞T-selective minor groove-binding agent distamycin prevented the TATA binding protein from binding to its A͞T-rich target site in the minor groove, but it was unable to inhibit the major groove-binding TF EGR from binding to its G͞C-rich sequence (2). However, distamycin could prevent major groove-binding homeodomain peptides from binding to their A͞T-rich sites (3).…”

mentioning

confidence: 99%

Inhibition of transcription factor-DNA complexes and gene expression by a microgonotropen

White

Satz

Bruice

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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Developing minor groove-binding drugs to selectively inhibit transcription factor (TF)͞DNA interactions and accompanying gene expression is a current goal in drug development studies. Equipping minor groove-binding agents with positively charged, major groove-contacting side chains yields microgonotropens (MGTs). Previously, we demonstrated that MGTs were superior inhibitors of TF͞DNA complexes in cell-free assays compared with ''classical'' groove binders, but MGTs showed limited ability to inhibit gene expression. To determine what chemical characteristics contribute to or improve activity, we evaluate five MGTs for their effectiveness in inhibiting TF complex formation and resultant transcription by using the c-fos serum response element (SRE) as a target. MGT L1 binds DNA via a bisbenzimidazole equipped with a tripyrrole moiety. It is compared with analog L2, which has been functionalized with propylamines on each of the three pyrroles. L2, which binds DNA at subpicomolar concentrations, was at least three orders of magnitude more potent than L1 at inhibiting TF binding to the c-fos SRE in cell-free assays. Unlike L1 and previous MGTs, L2 also inhibited endogenous c-fos expression in NIH 3T3 cells at micromolar levels. Structure͞activity relationships suggest that, although the tripyrrole͞polyamine functional group of L2 may be largely responsible for its inhibition of TF complexes in cell-free assays, its bisbenzimidazole moiety appears to impart improved cellular uptake and activity. These findings make L2 a promising lead candidate for future, rational MGT design.

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“…Failure to inhibit transcription in vivo could be caused by insufficient nuclear concentrations of the inhibitor or possibly by the presence of numerous competing TCCT sites in the eukaryotic genome. Recently, other minor groove binders have been studied for their effects on the transcriptional machinery (33,34 …”

Section: Discussionmentioning

confidence: 99%

Sequence-selective carbohydrate-DNA interaction: dimeric and monomeric forms of the calicheamicin oligosaccharide interfere with transcription factor function.

Liu

Smith

Ajito

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

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The synthetic oligosaccharide moiety of the antibiotic calicheamicin and the head-to-head dimer of this oligosaccharide are known to bind to the minor groove of DNA in a sequence-selective manner preferring distinct target sequences. We tested these carbohydrates for their ability to interfere with transcription factor function. The The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.carbohydrates can interfere with the sequence-specific binding of transcription factors to DNA and with the activation of transcription. We find that the dimer of the calicheamicin oligosaccharide is a much more effective inhibitor of biological activity than is the monomer. MATERIALS AND METHODSCalicheamicin Carbohydrates. The aryltetrasaccharide of calicheamicin was obtained by total synthesis as described (12,17). The synthesis of the head-to-head dimer of this compound has also been reported (18). Structure and purity of the carbohydrates were verified by thin-layer chromatography and IH NMR spectroscopy.Electrophoretic Mobility Shift Assays. The oligonucleotides used in electrophoretic mobility shift assays are shown in Table 1. The AP-1 binding site is derived from the human collagenase gene promoter. It does not contain a TCCT sequence and serves as a control for nonspecific binding of the carbohydrate. In the AP-1(TCCT) and the AP-1(TCCT)2 oligonucleotides, TCCT sequences (doubly underlined in Table 1) were constructed near the AP-1 consensus. The AP-1(TCCT) oligonucleotide contains one TCCT site, five nucleotides 5' to the consensus, and the AP-1(TCCT)2 oligonucleotide contains two TCCT sites, one immediately 5' to the consensus, and a second one six nucleotides upstream. AP-1(DM) contains the optimal dimer DNA binding sequence AGGAAGTCCT im-

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Distamycin-induced inhibition of homeodomain-DNA complexes.

Abstract: The mobility shift assay was used to study the

Cited by 87 publications

References 77 publications

High Mobility Group I Proteins Interfere with the Homeodomains Binding to DNA

High Mobility Group I Proteins Interfere with the Homeodomains Binding to DNA

Inhibition of transcription factor-DNA complexes and gene expression by a microgonotropen

Sequence-selective carbohydrate-DNA interaction: dimeric and monomeric forms of the calicheamicin oligosaccharide interfere with transcription factor function.

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