Your browser doesn't support javascript.
loading
Development and characterisation of SMURF2-targeting modifiers.
Manikoth Ayyathan, Dhanoop; Levy-Cohen, Gal; Shubely, Moran; Boutros-Suleiman, Sandy; Lepechkin-Zilbermintz, Veronica; Shokhen, Michael; Albeck, Amnon; Gruzman, Arie; Blank, Michael.
Afiliación
  • Manikoth Ayyathan D; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • Levy-Cohen G; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • Shubely M; Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
  • Boutros-Suleiman S; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
  • Lepechkin-Zilbermintz V; Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
  • Shokhen M; Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
  • Albeck A; Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
  • Gruzman A; Department of Chemistry, Bar-Ilan University, Ramat Gan, Israel.
  • Blank M; Laboratory of Molecular and Cellular Cancer Biology, Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel.
J Enzyme Inhib Med Chem ; 36(1): 401-409, 2021 Dec.
Article en En | MEDLINE | ID: mdl-33430646
The C2-WW-HECT-domain E3 ubiquitin ligase SMURF2 emerges as an important regulator of diverse cellular processes. To date, SMURF2-specific modulators were not developed. Here, we generated and investigated a set of SMURF2-targeting synthetic peptides and peptidomimetics designed to stimulate SMURF2's autoubiquitination and turnover via a disruption of the inhibitory intramolecular interaction between its C2 and HECT domains. The results revealed the effects of these molecules both in vitro and in cellulo at the nanomolar concentration range. Moreover, the data showed that targeting of SMURF2 with either these modifiers or SMURF2-specific shRNAs could accelerate cell growth in a cell-context-dependent manner. Intriguingly, a concomitant cell treatment with a selected SMURF2-targeting compound and the DNA-damaging drug etoposide markedly increased the cytotoxicity produced by this drug in growing cells. Altogether, these findings demonstrate that SMURF2 can be druggable through its self-destructive autoubiquitination, and inactivation of SMURF2 might be used to affect cell sensitivity to certain anticancer drugs.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ubiquitina-Proteína Ligasas / Inhibidores Enzimáticos / Desarrollo de Medicamentos / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Ubiquitina-Proteína Ligasas / Inhibidores Enzimáticos / Desarrollo de Medicamentos / Antineoplásicos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: J Enzyme Inhib Med Chem Asunto de la revista: BIOQUIMICA / QUIMICA Año: 2021 Tipo del documento: Article País de afiliación: Israel Pais de publicación: Reino Unido