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Golgi-SNARE GS28 potentiates cisplatin-induced apoptosis by forming GS28/MDM2/p53 complexes and by preventing the ubiquitination and degradation of p53.
MedLine Citation:
PMID:  22397410     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
In the present study, we observed that the Golgi-SNARE GS28 forms a complex with p53 in HEK293 cells. Given that p53 represents a tumor suppressor involved in sensitivity to various chemotherapeutic drugs, we examined whether GS28 may be implicated in resistance to the DNA-damaging drug cisplatin, whereas no sensitization effect was noted following treatment with the mitotic spindle-damaging drugs vincristine and taxol. Indeed, knockdown of GS28 using short-hairpin RNA <st2:citation>(shGS28)</st2:citation> induced resistance to cisplatin in HEK293 cells. On the other hand, overexpression of GS28 sensitized HEK293 cells to cisplatin. Accordingly, we observed that knockdown of GS28 reduced the accumulation of p53 and its pro-apoptotic target Bax. Conversely, GS28 overexpression induced the accumulation of p53 and Bax as well as the pro-apoptotic phosphorylation of p53 on Ser46. Further experiments showed that these cellular responses could be abrogated by the p53 inhibitor PFT-α, indicating that GS28 may affect the stability and activity of p53. The modulatory effects of GS28 on cisplatin sensitivity and p53 stability were absent in lung cancer H1299 cells which are p53-null. As expected, ectopic expression of p53 in H1299 cells restored the modulatory effects of GS28 on sensitivity to cisplatin. In addition, GS28 was found to form a complex with the p53 E3 ligase MDM2 in H1299 cells. Furthermore, the ubiquitination of p53 was reduced by overexpression of GS28 in cells, confirming that GS28 enhances the stability of the p53 protein. Taken together, these results suggest that GS28 may potentiate cells to DNA damage-induced apoptosis by inhibiting the ubiquitination and degradation of p53.
Authors:
Nian-Kang Sun; Shang-Lang Huang; Kun-Yi Chien; Chuck C-K Chao
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-8
Journal Detail:
Title:  The Biochemical journal     Volume:  -     ISSN:  1470-8728     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-3-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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