Michael J Salcius

Yale University, New Haven, Connecticut, United States

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Publications (2)12.3 Total impact

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    ABSTRACT: The development of new ligands for the oncoprotein Ras can provide tools for the study of this important signaling component or potentially serve as therapeutic agents for the treatment of Ras-associated diseases. Herein, we report a peptidic Ras ligand identified through naïve phage display. Panning a phage library with a diversity of 10(9) transormants successfully identified a peptide dodecamer that contains two internal consensus motifs and binds Ras in both the active GTP- and inactive GDP-bound conformations with low micromolar dissociation constants. The dodecamer does not alter the intrinsic GTPase activity of Ras, does not compete for Ras binding to the Ras binding domain of Raf, and does not alter cell viability. This novel Ras ligand has the potential to serve in the development of higher-affinity ligands and chemical tools targeting Ras.
    ChemBioChem 03/2010; 11(4):517-22. · 3.74 Impact Factor
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    ABSTRACT: Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Treatment of estrogen-dependent breast cancer cells with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G(1) arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells induced G(1) arrest but did not affect cells that do not express AR. Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR, respectively.
    Oncogene 10/2008; 27(57):7201-11. · 8.56 Impact Factor

Publication Stats

28 Citations
12.30 Total Impact Points

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Institutions

  • 2008
    • Yale University
      • Department of Molecular, Cellular and Developmental Biology
      New Haven, Connecticut, United States