|At present eight distinct SMAD proteins are known. They can be divided into three different functional classes: (i) the receptor activated R-SMADs (SMAD 1, 2, 3, 5, and 8), (ii) the co-mediator Co-SMAD (SMAD 4) and (iii) the inhibitory I-SMADs (SMAD 6 and 7). In non-activated cells, R-SMADs are predominantly localized in the cytoplasm, Co-SMADs are equally distributed in the cytoplasm and the nucleus and I-SMADs are found mostly in the nucleus. Upon stimulation of receptors of the TGFβ superfamily RSMADs become phosphorylated and activated. They undergo dimerization and form heterotrimers with Co-SMADs. This complex then translocates to the nucleus and influences the transcriptional regulation (Lebrin et al, 2005).
The TGFβ-family members comprise about 30 members in the mammalian system and can be devided [sic] into two groups, the TGFβ/activin family and the BMP group (bone morphogenetic protein). Each group is responsible for activation of different SMAD isoforms.
The recruitment of SMADs to DNA is regulated by cooperation with other transcription factors. These factors facilitate binding of SMADs to DNA. One transcription factor that can interact with SMAD and that is expressed in heart is AP-1. TGFβ is released under several pathophysiologic conditions like ischemia/reperfusion and cardiomyopathy (Poncelet et al., 2001), which simultaneously activate SMAD and AP-1. Both factors, AP-1 and SMAD mediate enhanced expression of TGFβ responsive genes, like collagen (Ross et al, 2004), c-Jun (Lopez-Rovira et al, 2000), endothelin-1 (Sanchez-Elsner et al, 2001). Another functional aspect of AP-1/SMAD signaling is the induction of apoptosis in TGFβ stimulated cells (Kon et al, 1999; Arthur et al, 2000; Euler et al., 2006) and involved in NO induced apoptosis in adult rat cardiomyocytes. Therefore, TGFβ family members may induce apoptosis in this pathway.
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At present eight distinct SMAD proteins are known. They can be divided into three different functional classes: (i) the receptor-activated R-SMADs (SMAD 1, 2, 3, 5, and 8), (ii) the co-mediator Co-SMADs (SMAD 4), and (iii) the inhibitory I-SMADs (SMAD 6 and 7). [...]
In non-activated cells, R-SMADs are predominantly localized in the cytoplasm, Co-SMADs are equally distributed in the cytoplasm and the nucleus, and I-SMADs are found mostly in the nucleus. Upon stimulation of receptors of the TGFβ superfamily, R-SMADs become phosphorylated and activated, undergoing dimerization and thereafter forming heterotrimers with Co-SMADs. This complex then translocates to the nucleus and influences transcriptional regulation .
The TGFβfamily comprises around 30 members in the mammalian system and can be divided into two groups: the TGFβ/activin family and the BMP group. Each group is responsible for activation of different SMAD isoforms (Fig. 3).
Consequently, recruitment of SMADs to DNA is regulated by cooperation with other transcription factors. These factors facilitate binding of SMADs to DNA [...]
One of the first transcription factors detected to interact with SMADs is the activator protein AP-1. [...]
TGFβ is a cytokine that is released under several pathophysiologic conditions and that simultaneously activates SMAD and AP-1. Both AP-1 and SMAD mediate enhanced expression of TGFh-responsive genes, such as collagen , c-Jun , endothelin-1 , or peroxisome proliferator activated receptor gamma (PPARg) . [...] Another functional consequence of the concerted action of AP-1/SMAD signaling is the induction of apoptosis in TGFβ-stimulated cells [44,48]: in isolated adult cardiomyocytes, involvement of AP-1/SMAD signaling in apoptosis induction by TGFβ or nitric oxide was demonstrated .
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