SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4 - PubMed (original) (raw)

. 2003 Aug 15;278(33):31043-8.

doi: 10.1074/jbc.C300112200. Epub 2003 Jun 17.

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SUMO-1/Ubc9 promotes nuclear accumulation and metabolic stability of tumor suppressor Smad4

Xia Lin et al. J Biol Chem. 2003.

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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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