Lani
09-19-2007, 07:22 AM
1: Cancer Res. 2007 Sep 15;67(18):8716-24.
Degradation of HER2 by Cbl-Based Chimeric Ubiquitin Ligases.
Li X, Shen L, Zhang J, Su J, Shen L, Liu X, Han H, Han W, Yao L.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology.
Targeting disease-causing proteins for ubiquitination and degradation by chimeric molecules represents a promising alternative therapeutic strategy in cancer. Here, several Cbl-based chimeric ubiquitin ligases were recombined to achieve effective down-regulation of HER2. These chimeric molecules consisted of the Cbl NH(2)-terminal tyrosine kinase binding domain, linker, and RING domain, with the Src homology 2 domain replaced with that from growth factor receptor binding protein 2 (Grb2), Grb7, p85, or Src. The chimeric proteins not only interacted with HER2 but also enhanced the down-regulation of endogenous overexpressed HER2. After the chimeric proteins were introduced into HER2-overexpressing breast cancer SK-BR-3 cells or ovarian cancer SK-OV-3 cells, they effectively promoted HER2 ubiquitination and degradation in a RING finger domain-dependent manner. Consequently, expression of these chimeric molecules led to an inhibition of colony formation, increased the proportion of cells in the G(1) cycle, and suppressed tumorigenicity. Collectively, our findings suggest that the Cbl-based chimeric ubiquitin ligases designed in the present study may represent a novel approach for the targeted therapy of HER2-overexpressing cancers. [Cancer Res 2007;67(18):8716-24].
PMID: 17875712 [PubMed - in process]
ubiquitin has been likened to the garbage collectors who send abnormal and diseased proteins to the garbage processing plant, or proteasome
this involves getting rid of the overexpressed her2 receptors which are driving the breast cancer to grow and spread. Further reading of the article
explained that this treatment may work even better when combined with a
HSP90 inhibitors like 17AAG, geldenamycin or the new one in trials (name escapes me for now, but believe it started with an "a" from Kosan Pharmaceuticals recently discussed here.
Degradation of HER2 by Cbl-Based Chimeric Ubiquitin Ligases.
Li X, Shen L, Zhang J, Su J, Shen L, Liu X, Han H, Han W, Yao L.
State Key Laboratory of Cancer Biology, Department of Biochemistry and Molecular Biology.
Targeting disease-causing proteins for ubiquitination and degradation by chimeric molecules represents a promising alternative therapeutic strategy in cancer. Here, several Cbl-based chimeric ubiquitin ligases were recombined to achieve effective down-regulation of HER2. These chimeric molecules consisted of the Cbl NH(2)-terminal tyrosine kinase binding domain, linker, and RING domain, with the Src homology 2 domain replaced with that from growth factor receptor binding protein 2 (Grb2), Grb7, p85, or Src. The chimeric proteins not only interacted with HER2 but also enhanced the down-regulation of endogenous overexpressed HER2. After the chimeric proteins were introduced into HER2-overexpressing breast cancer SK-BR-3 cells or ovarian cancer SK-OV-3 cells, they effectively promoted HER2 ubiquitination and degradation in a RING finger domain-dependent manner. Consequently, expression of these chimeric molecules led to an inhibition of colony formation, increased the proportion of cells in the G(1) cycle, and suppressed tumorigenicity. Collectively, our findings suggest that the Cbl-based chimeric ubiquitin ligases designed in the present study may represent a novel approach for the targeted therapy of HER2-overexpressing cancers. [Cancer Res 2007;67(18):8716-24].
PMID: 17875712 [PubMed - in process]
ubiquitin has been likened to the garbage collectors who send abnormal and diseased proteins to the garbage processing plant, or proteasome
this involves getting rid of the overexpressed her2 receptors which are driving the breast cancer to grow and spread. Further reading of the article
explained that this treatment may work even better when combined with a
HSP90 inhibitors like 17AAG, geldenamycin or the new one in trials (name escapes me for now, but believe it started with an "a" from Kosan Pharmaceuticals recently discussed here.