Yb1 Yy1

Proto-oncoprotein; Smads corepressor; recruits HDAC; binds Smad4 L3 loop to inhibit Smad4 association with Smad2/3; stabilizes inactive Smads on SBE Forkhead-associated nuclear protein; competes with p300 to bind Smad4; upregulates cyclin D expression Proto-oncoprotein and potential tumor suppressor; Smads corepressor; recruits HDAC Binds and inhibits Smad3 transcriptional activity Homeo-domain factor; Smads corepressor; recruits HDAC, mSin3A and CtBP

Y box-binding protein; represses TGF-p-stimulated a2(I) procollagen gene transcription by interfering with Smad3 binding to DNA and disrupting the Smad3-p300 interaction

Interacts with Smads; inhibits TGF-P- and BMP-induced cell differentiation by repressing Smad activity in a gene-specific manner

Akiyoshi etal., 1999; Luo et al., 1999; Nomura et al., 1999; Sun et al., 1999a; Wu et al., 2002; Suzuki et al., 2004 Kim et al., 2000

Stroschein etal., 1999; Sun etal., 1999 Grimsby et al., 2004

Wotton et al., 1999a; 1999b; Melhuish and Wotton, 2000; Wotton et al., 2001 Higashi et al., 2003

Kurisaki et al., 2003

Despite being highly homologous with Smad3, Smad2 is unable to bind to DNA due to the insertion of the exon 3-encoded extra 30 amino acids present immediately before the DNA binding hairpin (Dennler et al., 1998; Shi et al., 1998; Yagi et al., 1999; Shi, 2001). If exon 3 is removed, as found in an alternatively spliced Smad2, it can then bind to the SBE sequence (Yagi et al., 1999). The transcript of this alternatively spliced variant Smad2 is present in certain cells and tissues at a level of about 1/10 of full length Smad2 (Yagi et al., 1999). Recent studies have shown that the full length Smad2 and this short form of Smad2 are coexpressed throughout mouse development (Dunn et al., 2005). Further studies in mouse indicate that the short isoform of Smad2 or Smad3, but not full-length Smad2, activates all essential target genes downstream of TGF-P-related ligands (Dunne/al., 2005). Similarly, as described above, genome-wide microarray screening of TGF-[3 responsive genes by comparing wild type with Smad2 or Smad3 abalated fibroblasts have indicated that Smad3 is an essential mediator of TGF-P signal transduction and transcriptional regulation (Yang et al., 2003). Ongoing studies by RNAi approach in a few laboratories reach the same conclusion for certain other cell types analyzed. Thus, Smad3 plays a critical physiological role in mediating TGF-P responses.

The DNA binding activity of Smad3 is regulated by protein kinase C. PKC can phosphorylate Smad3 at Ser 37 and Ser 70 both in vivo and in vitro (Fig. 11.3) (Yakymovych et al., 2001). Phosphorylation of Smad3 by PKC abrogates its DNA-binding activity and thus inhibits the transcriptional responses (Yakymovych et al., 2001). PKC can also phosphorylate Smad2 at the analogous Ser 47 and Ser 110 (Yakymovych et al., 2001). The physiological significance of PKC phosphorylation of Smad2 remains to be elucidated.

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