10 Transcriptional Control via Smads

Abstract

Transforming growth factor-β (TGF-β) family signaling controls diverse developmental processes and the pathogenesis of many diseases, including cancer and autoimmune and fibrotic diseases. TGF-β and related proteins signal through heteromeric serine-threonine kinase receptors at the cell surface and intracellular effectors called Smads. Advancement in the knowledge of Smads as key TGF-β signal transducers and transcription factors has made it possible to establish a comprehensive model for how the conceptually simple Smad signaling pathways control a broad range of cellular responses in response to a large family of TGF-β ligands (Derynck and Zhang 2003; Shi and Massagué 2003; ten Dijke and Hill 2004; Feng and Derynck 2005). Smads orchestrate the transcription of specific gene networks through interactions with cooperating sequence-specific DNA-binding transcription factors, specific DNA response elements, and non-DNA-binding transcription coactivators or corepressors that act to modify local chromatin structure and/or engage the basal transcription machinery (Fig. 1) (for reviews, see Feng and Derynck 2005; Massagué et al. 2005). Recent findings also suggest that the regulation of Smad activity through posttranslational modifications such as (de)phosphorylation, ubiquitylation, and sumoylation controls the magnitude and duration of TGF-β responses (Fig. 2) (for reviews, see Feng and Lin 2006; Schilling et al. 2006). This mechanism allows for specific yet robust gene activation or repression in response to TGF-β in a context-dependent manner. This chapter spotlights the properties of Smads as transcription factors.

DNA-BINDING PROPERTIES OF SMADS
Transcriptional activation is a highly regulated process requiring the rigorous interactions of DNA-binding transcription factors, coactivator proteins, and general transcription...