SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4.
J Biol Chem
; 278(33): 31043-8, 2003 Aug 15.
Article
in En
| MEDLINE
| ID: mdl-12813045
ABSTRACT
Tumor suppressor Smad4/DPC4 is a central intracellular signal transducer for transforming growth factor-beta (TGF-beta) signaling. We recently reported that transcriptional potential of Smad4 was regulated by SUMOylation in transfected HeLa cells (1), but the precise mechanism and function of Smad4 SUMOylation in TGF-beta signaling remain to be elucidated. Here, we describe the regulation of TGF-beta signaling by SUMOylation through the control of Smad4 metabolic stability and subcellular localization. We found that SUMO-1 overexpression strongly increases Smad4 levels, while inhibition of SUMOylation by small interfering RNA (siRNA)-mediated knockdown of the E2 enzyme Ubc9 reduces endogenous Smad4 levels. Concomitantly, SUMO-1 overexpression enhances and Ubc9 knockdown reduces levels of intranuclear Smad4, growth inhibitory response, as well as transcriptional responses to TGF-beta. Comparison of wild type and mutant forms of Smad4 for SUMOylation, ubiquitination, and half-life allows the conclusion that SUMO-1 modification serves to protect Smad4 from ubiquitin-dependent degradation and consequently enhances the growth inhibitory and transcriptional responses of Smad4.
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Collection:
01-internacional
Database:
MEDLINE
Main subject:
Trans-Activators
/
Tumor Suppressor Proteins
/
SUMO-1 Protein
/
DNA-Binding Proteins
Limits:
Humans
Language:
En
Journal:
J Biol Chem
Year:
2003
Document type:
Article
Affiliation country:
Estados Unidos