Uncoiling c-Jun coiled coils: Inhibitory effects of truncated Fos peptides on Jun dimerization and DNA binding in vitro

Abstract

c-Jun is an oncoprotein that comprises a portion of the AP-1 transcription factor and belongs to the basic-leucine zipper (bZIP) DNA binding protein family. Using peptides derived from the leucine zipper region of Fos, we have developed agents that inhibit Jun's DNA binding in the low micromolar range. Fos peptides that were effective inhibitors in the DNA binding assay were also found to inhibit cellular Jun binding to an AP-1 site in a luciferase reporter plasmid in MCF-7 cells. Size exclusion studies confirmed that peptides that inhibit the DNA binding of Jun also inhibit its dimerization. These peptides were found to have a cytotoxic effect on the MCF-7 cell line when delivered with the transfecting agent Tfx-50, possibly due to their role as transcription factor regulators.

Polymer Coiled-Coil Conjugates: Potential for Development as a New Class of Therapeutic “Molecular Switch”

“…Indeed, the mPEG-FosW C conjugate was inactive without the addition of Tfx-50. However, inherent toxicity seen for Tfx-50 at the concentration used (this control was not reported in previous studies) makes interpretation of these data difficult. Although, it is widely reported that nonspecific toxicity of transfection agents is greatly diminished when they are complexed to a payload (because of charge neutralization), it is clear that further definition of the cellular PK-PD relationships of mPEG-FosW C is needed to enable accurate quantitation of antitumor activity and thus aid the design of the most appropriate cytosolic delivery vector.…”

Peptide and Protein Recognition by Designed Molecules

“…The shape and substitution pattern of D-glucose were found to best present the Trp, Lys, and Phe side chains. Somatostatin receptor binding assays using 125 I-labeled somatostatin proved the mimicry of the structure, although with reduced activity relative to that of the natural hormone (∆IC 50 ≈ 10 4 ).…”

Protein–protein interactions: mechanisms and modification by drugs

“…So inhibitors of dimerization (IDs) may prevent formation of an active dimer. Such inhibitors have been discovered for three HIV enzymes (protease, reversed transcriptase, invertase; Bouras et al, 1999;Morris et al, 1999;Sourgen et al, 1996;Zutshi et al, 1998), ribonucleotide reductase (Liuzzi et al, 1994) and DNA polymerase (Digard et al, 1995) of herpes simplex virus, human gluthatione reductase (Nordhoff et al, 1997), phosphatidylinisitol 3-kinase (Eaton et al, 1998), virus capsid (Hilpert et al, 1999;Prevelige, 1998) and some others (Beaulieu et al, 1999;Brickner and Chmielewski, 1998;Chen et al, 2001;Crump et al, 1998;Findeis, 2000;Gay et al, 1999b;Ghosh et al, 1999;Hart et al, 1999;Kim et al, 1999;Li et al, 1998;Lou et al, 1999;Pacofsky et al, 1998;Prasanna et al, 1998;Saito et al, 1998;Singh et al, 2001;Vu et al, 1999;Usui et al, 1998;Yao et al, 1998Yao et al, , 1999. Most of the discovered IDs are peptides resembling dimer interfaces (Zutshi et al, 1998), although peptidomimetic molecules or small organic mol-ecules have also been found (Bouras et al, 1999;Findeis, 2000;Gay et al, 1999b;Sennequier et al, 1999;Souroujon and Mochly-Rosen, 1998;Yao et al, 1999;…”