IndraLab

"Loss of SMAD4 was associated with both decreased median disease-free survival (28months; 95% confidence interval, 16-40) months compared with 223months (95% confidence interval, 3-443months) for SMAD4 positive patients (P =.03) and decreased median disease specific survival (SMAD4 : 137 [95% confidence interval, 81-194] months versus SMAD4 positive : 204 [95% confidence interval, 143-264] months; P =.04)."

"The sumoylation of Smad4 alters its subnuclear localization, enhances its stability, and increases Smad4 mediated transcriptional activation."

"We also assessed whether a blockade of Smad4 SUMOylation could prevent Smad4 from binding to the TPM2 promoter in the brain."

"However, sumoylation of Smad4 can also suppress TGF-beta and BMP signaling by repressing the transcriptional activity of Smad4."

"In line with these results, Park etal 1 now found that Wip1 antagonized FGF induced Erk kinase Smad4 Thr277 phosphorylation and prevented Smad4 degradation."

"Furthermore, the over-expression of miR-224 in CRC cell lines decreased SMAD4 expression at the translational level and decreased SMAD4 driven luciferase reporter activity."

"In contrast to the inhibitory effects of K519 mono-ubiquitylation by ectodermin, Smad4 mono-ubiquitylation at K507 enhanced the capacity of Smad4 to form complexes with activated R-Smads."

"The loss of SMAD4 will abrogate the canonical TGF-b/SMAD4 signaling pathway (24) , and it may make pancreatic cancer more aggressive (25) ."

"Moreover, SMAD4 overexpression restored the mRNA and protein levels of SMAD4 and cell cycle related genes (P < 0.05)."

"Data in XREF_FIG show that Smad4 siRNA inhibits the expression of Smad4 in Panc1 cells (XREF_FIG), as well as the stress induced Smad4 like protein in BxPC3 cells (XREF_FIG)."

"Phosphorylation of the C-terminal serine residues in R-Smads by type I receptor kinases is a crucial step in TGF-b family signalling (Abdollah et al., 1997; Macias-Silva et al., 1996; Souchelnytskyi et al., 1997). The two most C-terminal serine residues become phosphorylated and, together with a third, non-phosphorylated serine residue, form an evolutionarily conserved SSXS motif in all R-Smads.... TGF-b and activin receptors phosphorylate Smad2 and Smad3, and BMP receptors phosphorylate Smad1, Smad5 and Smad8 (Chen et al., 1998) (Fig. 1). The consequence of R-Smad phosphorylation is the formation of oligomeric complexes with the Co-Smad, Smad4."

"Phosphorylation of the C-terminal serine residues in R-Smads by type I receptor kinases is a crucial step in TGF-b family signalling (Abdollah et al., 1997; Macias-Silva et al., 1996; Souchelnytskyi et al., 1997). The two most C-terminal serine residues become phosphorylated and, together with a third, non-phosphorylated serine residue, form an evolutionarily conserved SSXS motif in all R-Smads.... TGF-b and activin receptors phosphorylate Smad2 and Smad3, and BMP receptors phosphorylate Smad1, Smad5 and Smad8 (Chen et al., 1998) (Fig. 1). The consequence of R-Smad phosphorylation is the formation of oligomeric complexes with the Co-Smad, Smad4."

"Smads 3 and 4 have specifically been shown to take part in TGF-beta-mediated CTCF/Smads complex binding of the APP gene promoter that up-regulates APP expression In addition, TGF-beta has been shown to stimulate Smads interaction with the stimulating protein 1 (SP1) transcription factor"

"Alternatively, TSC-22 might act as transcriptional regu-lator as it binds to Smad4 via the TSC-box and modulates the transcriptional activity of Smad4 [XREF_BIBR]."