Identification of SAP155 as the target of GEX1A (Herboxidiene), an antitumor natural product.
ACS Chem Biol
; 6(3): 229-33, 2011 Mar 18.
Article
in En
| MEDLINE
| ID: mdl-21138297
ABSTRACT
GEX1A is a microbial product with antitumor activity. HeLa cells cultured with GEX1A accumulated p27(Kip) and its C-terminally truncated form p27*. GEX1A inhibited the pre-mRNA splicing of p27, producing p27* from the unspliced mRNA containing the first intron. p27* lacked the site required for E3 ligase-mediated proteolysis of p27, leading to its accumulation in GEX1A-treated cells. The accumulated p27* was able to bind to and inhibit the cyclin E-Cdk2 complex that causes E3 ligase-mediated degradation of p27, which probably triggers the accumulation of p27. By using a series of photoaffinity-labeling derivatives of GEX1A, we found that GEX1A targeted SAP155 protein, a subunit of SF3b responsible for pre-mRNA splicing. The linker length between the GEX1A pharmacophore and the photoreactive group was critical for detection of the GEX1A-binding protein. GEX1A serves as a novel splicing inhibitor that specifically impairs the SF3b function by binding to SAP155.
Full text:
1
Database:
MEDLINE
Main subject:
Phosphoproteins
/
Pyrans
/
Biological Products
/
Ribonucleoprotein, U2 Small Nuclear
/
Fatty Alcohols
/
Antineoplastic Agents
Type of study:
Diagnostic_studies
/
Prognostic_studies
Limits:
Humans
Language:
En
Year:
2011
Type:
Article