Disease relevance of Smad6

• Hyperplasia of the cardiac valves and outflow tract septation defects indicate a function for Smad6 in the regulation of endocardial cushion transformation [1].
• Targeted insertion of a LacZ reporter demonstrated that Smad6 expression is largely restricted to the heart and blood vessels, and that Madh6 mutants have multiple cardiovascular abnormalities [1].
• Smad6/Smurf1 overexpression in cartilage delays chondrocyte hypertrophy and causes dwarfism with osteopenia [2].
• Smad6 transgenic mice showed postnatal dwarfism with osteopenia and inhibition of Smad1/5/8 phosphorylation in chondrocytes [2].
• Immunocytochemical and immunoprecipitation studies demonstrate overlapping nuclear localization and physical interaction between Dlx3 and Smad6 in human choriocarcinoma cells and in differentiated trophoblasts from human placenta [3].

High impact information on Smad6

• The role of Smad6 in the homeostasis of the adult cardiovascular system is indicated by the development of aortic ossification and elevated blood pressure in viable mutants [1].
• Mating Smad6 and Smurf1 transgenic mice produced double-transgenic pups with more delayed endochondral ossification than Smad6 transgenic mice [2].
• Here, we generated transgenic mice overexpressing Smad6 in chondrocytes [2].
• Organ culture of cartilage rudiments showed that chondrocyte hypertrophy induced by BMP2 was inhibited in cartilage prepared from Smad6 transgenic mice [2].
• Biochemical experiments have shown that Smad6 and Smad ubiquitin regulatory factor 1 (Smurf1) block the signal transduction of bone morphogenetic proteins (BMPs) [2].

Biological context of Smad6

• We have isolated the mouse Smad6 promoter and identified the regions responsible for transcriptional activation by BMPs [4].
• Smad7 and Smad6 differentially modulate transforming growth factor beta -induced inhibition of embryonic lung morphogenesis [5].
• A role for smad6 in development and homeostasis of the cardiovascular system [1].
• Using a genome-wide computational screen based on the well characterized Scl +19 HSC enhancer, we have identified a related Smad6 enhancer that also targets expression to blood and endothelial cells in transgenic mice [6].
• Methylation of Smad6 by protein arginine N-methyltransferase 1 [7].

Anatomical context of Smad6

• AMSH interacts with Smad6, but not with R- and Co-Smads, upon BMP receptor activation in cultured cells [8].
• In contrast, Smad6 was selectively expressed at high levels, e.g. in intramembranous bone whereas Smad7 was prominent in seminiferous tubules of the testis, demonstrating distinct expression of these genes in non-cardiovascular tissues [9].
• Over-expression of Smad6 in chondrocytes causes delays in chondrocyte differentiation and maturation (<citeref rid="bib21">Horiki et al., 2004</citeref>) [10].
• Smad6 appears to play a modulatory role in the regulation of Dlx3-dependent gene transcription within placental trophoblasts [3].
• To elucidate the mechanism by which oxygen tension influences chondrocyte differentiation, the Smad pathway was examined using Smad6 overexpression adenovirus and Smad6 transgenic mice embryo forelimbs [11].

Regulatory relationships of Smad6

• Smad-6 overexpression significantly inhibited TGF-beta-stimulated chondrocyte proliferation, although proliferation was not completely abolished [12].

Other interactions of Smad6

• Smad5 knock-down also reduces the rise in Smad6 upon BMP7 [13].
• The expression of inhibitory Smads (Smad6 and 7) largely overlaps with receptor regulated Smads, indicating that negative feedback on BMP/TGF-beta signaling is critical throughout all stages of tooth morphogenesis [14].
• Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARgamma, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARgamma [15].

Analytical, diagnostic and therapeutic context of Smad6

• Immunocytochemistry showed overexpression of Smad-6 and -7 proteins in both the nucleus and cytoplasm [12].

References