Seite: 11, Zeilen: 3-25
|Quelle: Euler-Taimor and Heger 2006|
Seite(n): 17, 18, 19, Zeilen: 17:right col. 7-11.14-22; 18:left col. 30-33; 19:left col. 11-13.22-23; right col. 15-20.23-28
|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.
Arthur HM, Ure J, Smith AJ, Renforth G, Wilson DI, Torsney E, (2000) Endoglin, an ancillary TGFbeta receptor, is required for extraembryonic angiogenesis and plays a key role in heart development. Dev Biol 217: 42-53.
Euler T G and Heger J (2006) The complex pattern of SMAD signaling in the cardiovascular system. CVR page -----.
Kon A, Vindevoghel L, Kouba DJ, Fujimura Y, Uitto J, Mauviel A (1999) Cooperation between SMAD and NF-kappaB in growth factor regulated type VII collagen gene expression. Oncogene 18: 1837-44.
Lebrin F, Deckers M, Bertolino P, Ten Dijke P (2005) TGF-beta receptor function in the endothelium. Cardiovasc Res 65: 599-608.
Lopez-Rovira T, Chalaux E, Rosa JL, Bartrons R, Ventura F (2000) Interaction and functional cooperation of NF-kappa B with Smads. Transcriptional regulation of the junB promoter. J Biol Chem 275: 28937-28946.
Poncelet AC, Schnaper HW (2001) Sp1 and Smad proteins cooperate to mediate transforming growth factor-beta 1-induced alpha 2 (I) collagen expression in human glomerular mesangial cells. J Biol Chem 276: 6983-6992.
Ross RS (2004) Molecular and mechanical synergy: cross-talk between integrins and growth factor receptors. Cardiovasc Res 63: 381-390.
Sanchez-Elsner T, Botella LM, Velasco B, Corbi A, Attisano L, Bernabeu C (2001) Synergistic cooperation between hypoxia and transforming growth factor-beta pathways on human vascular endothelial growth factor gene expression. J Biol Chem 276: 38527-38535.
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 .
 Schneiders D, Heger J, Best P, Piper HM, Taimor G. SMAD proteins are involved in apoptosis induction in ventricular cardiomyocytes. Cardiovasc Res 2005;67:87–96.
 Liu F, Pouponnot C, Massague J. Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes. Genes Dev 1997;11:3157–67.
 Zhang Y, Feng XH, Derynck R. Smad3 and Smad4 cooperate with c-Jun/c-Fos to mediate TGF-beta-induced transcription. Nature 1998; 394:909–13.
 Yamamura Y, Hua X, Bergelson S, Lodish HF. Critical role of Smads and AP-1 complex in transforming growth factor-beta-dependent apoptosis. J Biol Chem 2000;275:36295–302.
 Wong C, Rougier-Chapman EM, Frederick JP, Datto MB, Liberati N.T, Li JM, et al. Smad3–Smad4 and AP-1 complexes synergize in transcriptional activation of the c-Jun promoter by transforming growth factor beta. Mol Cell Biol 1999;19:1821–30.
 Rodriguez-Pascual F, Redondo-Horcajo M, Lamas S. Functional cooperation between Smad proteins and activator protein-1 regulates transforming growth factor-beta-mediated induction of endothelin-1 expression. Circ Res 2003;92:1288–95.
 Fu M, Zhang J, Lin Y, Zhu X, Zhao L, Ahmad M, et al. Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads. Biochem J 2003;370:1019 – 25.
 Arsura M, Panta GR, Bilyeu JD, Cavin LG, Sovak MA, Oliver AA, et al. Transient activation of NF-kappaB through a TAK1/IKK kinase pathway by TGF-beta1 inhibits AP-1/SMAD signaling and apoptosis: implications in liver tumor formation. Oncogene 2003;22:412–25.
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