The inhibition of Stat5 by a peptide aptamer ligand specific for the DNA binding domain prevents target gene transactivation and the growth of breast and prostate tumor cells

  • The signal transducer and activator of transcription Stat5 is transiently activated by growth factor and cytokine signals in normal cells, but its persistent activation has been observed in a wide range of human tumors. Aberrant Stat5 activity was initially observed in leukemias, but subsequently also found in carcinomas. We investigated the importance of Stat5 in human tumor cell lines. shRNA mediated downregulation of Stat5 revealed the dependence of prostate and breast cancer cells on the expression of this transcription factor. We extended these inhibition studies and derived a peptide aptamer (PA) ligand, which directly interacts with the DNA-binding domain of Stat5 in a yeast-two-hybrid screen. The Stat5 specific PA sequence is embedded in a thioredoxin (hTRX) scaffold protein. The resulting recombinant protein S5-DBD-PA was expressed in bacteria, purified and introduced into tumor cells by protein transduction. Alternatively, S5-DBD-PA was expressed in the tumor cells after infection with a S5-DBD-PA encoding gene transfer vector. Both strategies impaired the DNA-binding ability of Stat5, suppressed Stat5 dependent transactivation and caused its intracellular degradation. Our experiments describe a peptide based inhibitor of Stat5 protein activity which can serve as a lead for the development of a clinically useful compound for cancer treatment.

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Metadaten
Author:Axel Weber, Corina Borghouts, Christian BrendelGND, Richard Moriggl, Natalia Delis, Boris Brill, Vida VafaizadehORCiDGND, Bernd GronerGND
URN:urn:nbn:de:hebis:30:3-324088
DOI:https://doi.org/10.3390/ph6080960
ISSN:1424-8247
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/24276378
Parent Title (English):Pharmaceuticals
Publisher:MDPI
Place of publication:Basel
Document Type:Article
Language:English
Date of Publication (online):2013/08/20
Date of first Publication:2013/08/20
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2013/12/02
Tag:RNA interference (RNAi); inhibition of DNA-binding; peptide aptamer (PA); prostate and breast cancer cell lines; protein transduction; signal transducer and activator of transcription 5 (Stat5); yeast-two-hybrid (Y2H)
Volume:6
Issue:8
Page Number:28
First Page:960
Last Page:987
Note:
Copyright © 2013 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
HeBIS-PPN:36333422X
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 3.0