動脈管壁中的平滑肌細胞，除了調控血壓此一重要的生理功能外，血管平滑肌細胞對於阻塞型血管疾病(例如：動脈硬化)的形成，也扮演很重要的角色。第二型富含半胱胺酸蛋白質主要表現在動脈平滑肌細胞中，其功能為限制血管平滑肌細胞移行，以保護血管免於病理性的血管內皮層增生。轉化生長因子β(Transforming Growth Factor β)為一多功能生長因子，動脈硬化形成時，轉化生長因子β透過其下游的許多訊息傳遞路徑參與其中，我們先前的研究發現，轉化生長因子β可增加第二型富含半胱胺酸蛋白質的表現，但其中調控的訊息傳遞路徑，仍尚待釐清。本篇研究旨在探討轉化生長因子β調控第二型富含半胱胺酸蛋白質表現之分子機制。以轉化生長因子β刺激血管平滑肌細胞後，除了會增加傳統的訊息傳遞分子Smad2及Smad3的磷酸化外，也會增加ATF2的磷酸化蛋白表現。利用RNA干擾(small interfering RNA)技術減少Smad2/3及ATF2的表現後，皆能有效地減少轉化生長因子β所增加的第二型富含半胱胺酸蛋白質表現，顯示Smad2/3及ATF2皆參與了轉化生長因子β對第二型富含半胱胺酸蛋白質的調控。不論利用第一型轉化生長因子β接受器激酶的抑制劑(SB431542)，抑制接受器上的激酶活性;或是利用RNA干擾技術，減少第一型轉化生長因子β接受器的表現，皆可有效降低轉化生長因子β所引起的Smad2/3磷酸化，但並不影響ATF2的磷酸化，由此可知，只有Smad2/3的磷酸化與第一型轉化生長因子β接受器有關，但ATF2的磷酸化與第一型轉化生長因子β接受器無關。利用Src家族酪氨酸激酶抑制劑(SU6656)，可降低轉化生長因子β所引起的RhoA和ATF2的活化，但不影響Smad2的活化。阻斷RhoA下游主要訊息分子－ROCK的活性，亦能降低轉化生長因子β所引起的ATF2磷酸化及第二型富含半胱胺酸蛋白質表現，但Smad2的磷酸化則不受影響。我們更進一步地發現，JNK激酶抑制劑(SP600125)也能抑制轉化生長因子β所引起的ATF2磷酸化及第二型富含半胱胺酸蛋白質表現，不過轉化生長因子β所引起的JNK激酶活化，也會受到ROCK抑制劑的阻斷。這些結果顯示，轉化生長因子β透過其第二型接受器，活化下游的Src家族酪氨酸激酶/RhoA/ROCK/JNK此一訊息傳遞路徑，調控ATF2的磷酸化。經由啟動子活性分析可知，轉化生長因子β透過啟動子上，CRE和SBE這兩個相鄰的結合位置，來增加第二型富含半胱胺酸蛋白質表現。上述的結果顯示，轉化生長因子β利用兩條不同的訊息傳遞路徑，分別作用在啟動子上CRE和SBE兩個結合位置，協同調控第二型富含半胱胺酸蛋白質表現，此一轉化生長因子β對於平滑肌細胞基因的特殊調控方式，是首度被報導。

Vascular smooth muscle cells (VSMCs) of the arterial wall play a critical role in the development of occlusive vascular diseases. Cysteine-rich protein 2 (CRP2) is a VSMC-expressed LIM-only protein, which functionally limits VSMC migration and protects against pathological vascular remodeling. The multifunctional cytokine TGFβ has been implicated to play a role in the pathogenesis of atherosclerosis through numerous downstream signaling pathways. We showed previously that TGFβ upregulates CRP2 expression; however, the detailed signaling mechanisms remain unclear. TGFβ treatment of VSMCs activated both Smad2/3 and ATF2 phosphorylation. Individually knocking down Smad2/3 or ATF2 pathways with siRNA impaired the TGFβ induction of CRP2, indicating that both contribute to CRP2 expression. Inhibiting TβRI kinase activity by SB431542 or TβRI knockdown abolished Smad2/3 phosphorylation but did not alter ATF2 phosphorylation, indicating while Smad2/3 phosphorylation was TβRI-dependent ATF2 phosphorylation was independent of TβRI. Inhibiting Src kinase activity by SU6656 suppressed TGFβ-induced RhoA and ATF2 activation but not Smad2 phosphorylation. Blocking ROCK activity, the major downstream target of RhoA, abolished ATF2 phosphorylation and CRP2 induction but not Smad2 phosphorylation. Furthermore, JNK inhibition with SP600125 reduced TGFβ-induced ATF2 (but not Smad2) phosphorylation and CRP2 protein expression while ROCK inhibition blocked JNK activation. These results indicate that downstream of TβRII, Src family kinase-RhoA-ROCK-JNK signaling pathway mediates TβRI-independent ATF2 activation. Promoter analysis revealed that the TGFβ induction of CRP2 was mediated through the CRE and SBE promoter elements that were located in close proximity. Our results demonstrate that two signaling pathways downstream of TGFβ converge on the CRE and SBE sites of the Csrp2 promoter to cooperatively control CRP2 induction in VSMCs, which represents a previously unrecognized mechanism of VSMC gene induction by TGFβ.

Adam, P.J., Regan, C.P., Hautmann, M.B., and Owens, G.K. (2000). Positive- and negative-acting Kruppel-like transcription factors bind a transforming growth factor β control element required for expression of the smooth muscle cell differentiation marker SM22α in vivo. J. Biol. Chem. 275, 37798-37806.
Arber, S., Halder, G., and Caroni, P. (1994). Muscle LIM protein, a novel essential regulator of myogenesis, promotes myogenic differentiation. Cell 79, 221-231.
Arber, S., Hunter, J.J., Ross, J., Jr., Hongo, M., Sansig, G., Borg, J., Perriard, J.C., Chien, K.R., and Caroni, P. (1997). MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure. Cell 88, 393-403.
Bhoumik, A., Takahashi, S., Breitweiser, W., Shiloh, Y., Jones, N., and Ronai, Z. (2005). ATM-dependent phosphorylation of ATF2 is required for the DNA damage response. Mol. Cell 18, 577-587.
Bandyopadhyay, B., Han, A., Dai, J., Fan, J., Li, Y., Chen, M., Woodley, D.T., and Li, W. (2011). TβRI/Alk5-independent TβRII signaling to ERK1/2 in human skin cells according to distinct levels of TβRII expression. J. Cell Sci. 124, 19-24.
Carvalho, R.L., Itoh, F., Goumans, M.J., Lebrin, F., Kato, M., Takahashi, S., Ema, M., Itoh, S., van Rooijen, M., Bertolino, P., et al. (2007). Compensatory signalling induced in the yolk sac vasculature by deletion of TGFβ receptors in mice. J. Cell Sci. 120, 4269-4277.
Chang, D.F., Belaguli, N.S., Iyer, D., Roberts, W.B., Wu, S.P., Dong, X.R., Marx, J.G., Moore, M.S., Beckerle, M.C., Majesky, M.W., et al. (2003a). Cysteine-rich LIM-only proteins CRP1 and CRP2 are potent smooth muscle differentiation cofactors. Dev. Cell 4, 107-118.
Chang, Y.F., Wei, J., Liu, X., Chen, Y.H., Layne, M.D., and Yet, S.F. (2003b). Identification of a CArG-independent region of the cysteine-rich protein 2 promoter that directs expression in the developing vasculature. Am. J. Physiol. Heart Circ. Physiol. 285, H1675-H1683.
Chen, C.H., Wu, M.L., Lee, Y.C., Layne, M.D., and Yet, S.F. (2010). Intronic CArG box regulates cysteine-rich protein 2 expression in the adult but not in developing vasculature. Arterioscler Thromb Vasc Biol. 30, 835-842.
Chen, C.H., Ho, Y.C., Ho, H.H., Chang, I.C., Kirsch, K.H., Chuang, Y.J., Layne, M.D., and Yet, S.F. (2013). Cysteine-rich protein 2 alters p130Cas localization and inhibits vascular smooth muscle cell migration. Cardiovasc. Res. 100, 461-471.
Chen, S., and Lechleider, R.J. (2004). Transforming growth factor-β-induced differentiation of smooth muscle from a neural crest stem cell line. Circ. Res. 94, 1195-1202.
Chen, S., Crawford, M., Day, R.M., Briones, V.R., Leader, J.E., Jose, P.A., and Lechleider, R.J. (2006). RhoA modulates Smad signaling during transforming growth factor-β-induced smooth muscle differentiation. J. Biol. Chem. 281, 1765-1770.
Cherepanova, O.A., Pidkovka, N.A., Sarmento, O.F., Yoshida, T., Gan, Q., Adiguzel, E., Bendeck, M.P., Berliner, J., Leitinger, N., and Owens, G.K. (2009). Oxidized phospholipids induce type VIII collagen expression and vascular smooth muscle cell migration. Circ. Res. 104, 609-618.
Cipollone, F., Fazia, M., Mincione, G., Lezzi, A., Pini, B., Cuccurullo, C., Ucchino, S., Spigonardo, F., Di Nisio, M., Cuccurullo, F., et al. (2004). Increased expression of Transforming growth factor-β1 as a stabilizing factor in human atherosclerotic plaques. Stroke. 35, 2253-2257.
Cho, S.G., Bhoumik, A., Broday, L., Ivanov, V., Rosenstein, B., and Ronai, Z. (2001). TIP49b, a regulator of activating transcription factor 2 response to stress and DNA damage. Mol. Cell Biol. 21, 8398-8413.
Corjay, M.H., Blank, R.S., and Owens, G.K. (1990). Platelet-derived growth factor-induced destabilization of smooth muscle α-actin mRNA. J. Cell. Physiol. 145, 391-397.
Deaton, R.A., Su, C., Valencia, T.G., and Grant, S.R. (2005). Transforming growth factor-β1-induced expression of smooth muscle marker genes involves activation of PKN and p38 MAPK. J. Biol. Chem. 280, 31172-31181.
Derynck, R., Gelbart, W.M., Harland, R.M., Heldin, C.H., Kern, S.E., Massague, J., Melton, D.A., Mlodzik, M., Padgett, R.W., Roberts, A.B., et al. (1996). Nomenclature: vertebrate mediators of TGFβ family signals. Cell 87, 173.
Derynck, R., and Feng, X.H. (1997). TGF-β receptor signaling. Biochim. Biophys. Acta 1333, F105-F150.
Doran, A.C., Meller, N., and McNamara, C.A. (2008). Role of smooth muscle cells in the initiation and early progression of atherosclerosis. Arterioscler. Thromb. Vasc. Biol. 28, 812-819.
Dziembowska, M., Danilkiewicz, M., Wesolowska, A., Zupanska, A., Chouaib, S., and Kaminska, B. (2007). Cross-talk between Smad and p38 MAPK signalling in transforming growth factor β signal transduction in human glioblastoma cells. Biochem. Biophys. Res. Commun. 354, 1101-1106.
Engel, M.E., McDonnell, M.A., Law, B.K., and Moses, H.L. (1999). Interdependent SMAD and JNK signaling in transforming growth factor-β-mediated transcription. J. Biol. Chem. 274, 37413-37420.
Feldman, L.J., Aguirre, L., Ziol, M., Bridou, J.P., Nevo, N., Michel, J.B., and Steg, P.G. (2000). Interleukin-10 inhibits intimal hyperplasia after angioplasty or stent implantation in hypercholesterolemic rabbits. Circulation 101, 908-916.
Gomez, D., and Owens, G.K. (2012). Smooth muscle cell phenotypic switching in atherosclerosis. Cardiovasc. Res. 95, 156-164.
Goumans, M.J., and Mummery, C. (2000). Functional analysis of the TGFβ receptor/Smad pathway through gene ablation in mice. Int. J. Dev. Biol. 44, 253-265.
Goumans, M.J., Liu, Z., and ten Dijke, P. (2009). TGF-β signaling in vascular biology and dysfunction. Cell Res. 19, 116-127.
Gozdecka, M., and Breitwieser, W. (2012). The role of ATF2 (activating transcription factor 2) in tumorigenesis. Biochem. Soc. Trans. 40, 230-234.
Grainger, D.J., Kemp, P.R., Metcalfe, J.C., Liu, A.C., Lawn, R.M., Williams, N.R., Grace, A.A., Schofield, P.M., and Chauhan, A. (1995). The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nat. Med. 1, 74-79.
Grubinger, M., and Gimona, M. (2004). CRP2 is an autonomous actin-binding protein. FEBS Lett. 557, 88-92.
Gunther, S., Alexander, R.W., Atkinson, W.J., and Gimbrone, M.A., Jr. (1982). Functional angiotensin II receptors in cultured vascular smooth muscle cells. J. Cell Biol. 92, 289-298.
Guo, X., and Chen, S.Y. (2012). Transforming growth factor-β and smooth muscle differentiation. World J. Biol. Chem. 3, 41-52.
Hautmann, M.B., Madsen, C.S., and Owens, G.K. (1997). A transforming growth factor β (TGFβ) control element drives TGFβ-induced stimulation of smooth muscle α-actin gene expression in concert with two CArG elements. J. Biol. Chem. 272, 10948-10956.
Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y.Y., Grinnell, B.W., Richardson, M.A., Topper, J.N., Gimbrone, M.A., Jr., Wrana, J.L., et al. (1997). The MAD-related protein Smad7 associates with the TGFβ receptor and functions as an antagonist of TGFβ signaling. Cell 89, 1165-1173.
Henke, P.K., DeBrunye, L.A., Strieter, R.M., Bromberg, J.S., Prince, M., Kadell, A.M., Sarkar, M., Londy, F., and Wakefield, T.W. (2000). Viral IL-10 gene transfer decreases inflammation and cell adhesion molecule expression in a rat model of venous thrombosis. J. Immunol. 164, 2131-2141.
Hirschi, K.K., Rohovsky, S.A., and D'Amore, P.A. (1998). PDGF, TGF-β, and heterotypic cell-cell interactions mediate endothelial cell-induced recruitment of 10T1/2 cells and their differentiation to a smooth muscle fate. J. Cell Biol. 141, 805-814.
Holycross, B.J., Blank, R.S., Thompson, M.M., Peach, M.J., and Owens, G.K. (1992). Platelet-derived growth factor-BB-induced suppression of smooth muscle cell differentiation. Circ. Res. 71, 1525-1532.
Hsu, C.C., and Hu, C.D. (2012). Critical role of N-terminal end-localized nuclear export signal in regulation of activating transcription factor 2 (ATF2) subcellular localization and transcriptional activity. J. Biol. Chem. 287, 8621-8632.
Jain, M.K., Fujita, K.P., Hsieh, C.M., Endege, W.O., Sibinga, N.E., Yet, S.F., Kashiki, S., Lee, W.S., Perrella, M.A., Haber, E., et al. (1996). Molecular cloning and characterization of SmLIM, a developmentally regulated LIM protein preferentially expressed in aortic smooth muscle cells. J. Biol. Chem. 271, 10194-10199.
Jain, M.K., Kashiki, S., Hsieh, C.M., Layne, M.D., Yet, S.F., Sibinga, N.E., Chin, M.T., Feinberg, M.W., Woo, I., Maas, R.L., et al. (1998). Embryonic expression suggests an important role for CRP2/SmLIM in the developing cardiovascular system. Circ. Res. 83, 980-985.
Kawasaki, H., Song, J., Eckner, R., Ugai, H., Chiu, R., Taira, K., Shi, Y., Jones, N., and Yokoyama, K.K. (1998). p300 and ATF-2 components of the DRF complex, which regulates retinoic acid- and E1A-mediated transcription of the c-jun gene in F9 cells. Genes Dev. 12, 233-245.
Kihara, T., Shinohara, S., Fujikawa, R., Sugimoto, Y., Murata, M., and Miyake, J. (2011). Regulation of cysteine-rich protein 2 localization by the development of actin fibers during smooth muscle cell differentiation. Biochem. Biophys. Res. Commun. 411, 96-101.
Kirchner, J., Forbush, K.A., and Bevan, M.J. (2001). Identification and characterization of thymus LIM protein: targeted disruption reduces thymus cellularity. Mol. Cell. Biol. 21, 8592-8604.
Kobayashi, K., Yokote, K., Fujimoto, M., Yamashita, K., Sakamoto, A., Kitahara, M., Kawamura, H., Maezawa, Y., Asaumi, S., Tokuhisa, T., et al. (2005). Targeted disruption of TGF-β-Smad3 signaling leads to enhanced neointimal hyperplasia with diminished matrix deposition in response to vascular injury. Circ. Res. 96, 904-912.
Lau, E., and Ronai, Z.A. (2012). ATF2-at the crossroad of nuclear and cytosolic functions. J. Cell Sci. 125, 2815-2824.
Li, X.Y., and Green, M.R. (1996). Intramolecular inhibition of activating transcription factor-2 function by its DNA-binding domain. Genes Dev. 10, 517-527
Lien, S.C., Usami, S., Chien, S., and Chiu, J.J. (2006). Phosphatidylinositol 3-kinase/Akt pathway is involved in transforming growth factor-β1-induced phenotypic modulation of 10T1/2 cells to smooth muscle cells. Cell. Signal. 18, 1270-1278.
Lin, D.W., Chang, I.C., Tseng, A., Wu, M.L., Chen, C.H., Patenaude, C.A., Layne, M.D., and Yet, S.F. (2008). Transforming growth factor β up-regulates cysteine-rich protein 2 in vascular smooth muscle cells via activating transcription factor 2. J. Biol. Chem. 283, 15003-15014.
Liu, G., Ding, W., Neiman, J., and Mulder, K.M. (2006a). Requirement of Smad3 and CREB-1 in mediating transforming growth factor-β (TGF β) induction of TGFβ 3 secretion. J. Biol. Chem. 281, 29479-29490.
Liu, H., Deng, X., Shyu, Y.J., Li, J.J., Taparowsky, E.J., and Hu, C.D. (2006b). Mutual regulation of c-Jun and ATF2 by transcriptional activation and subcellular localization. EMBO J. 25, 1058-1069.
Livingstone, C., Patel, G., and Jones, N. (1995). ATF-2 contains a phosphorylation-dependent transcriptional activation domain. EMBO J. 14, 1785-1797.
Lopez-Casillas, F., Wrana, J.L., and Massague, J. (1993). Betaglycan presents ligand to the TGFβ signaling receptor. Cell 73, 1435-1444.
Louis, H.A., Pino, J.D., Schmeichel, K.L., Pomies, P., and Beckerle, M.C. (1997). Comparison of three members of the cysteine-rich protein family reveals functional conservation and divergent patterns of gene expression. J. Biol. Chem. 272, 27484-27491.
Mack, C.P. (2011). Signaling mechanisms that regulate smooth muscle cell differentiation. Arterioscler. Thromb. Vasc. Biol. 31, 1495-1505.
Majesky, M.W., Lindner, V., Twardzik, D.R., Schwartz, S.M., and Reidy, M.A. (1991). Production of transforming growth factor β 1 during repair of arterial injury. J. Clin. Invest. 88, 904-910.
Mallat, Z., Gojova, A., Marchiol-Fournigault, C., Esposito, B., Kamate, C., Merval, R., Fradelizi, D., and Tedgui, A. (2001). Inhibition of transforming growth factor-β signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ. Res. 89, 930-934.
Massague, J. (1998). TGF-β signal transduction. Annu. Rev. Biochem. 67, 753-791.
Mazighi, M., Pelle, A., Gonzalez, W., Mtairag el, M., Philippe, M., Henin, D., Michel, J.B., and Feldman, L.J. (2004). IL-10 inhibits vascular smooth muscle cell activation in vitro and in vivo. Am. J. Physiol. Heart Circ. Physiol. 287, H866-H871.
McCaffrey, T.A. (2000) TGF-βs and TGF-β receptors in atherosclerosis. Cytokine Growth Factor Rev. 11, 103-114.
Moustakas, A., and Heldin, C.H. (2005). Non-Smad TGF-β signals. J. Cell Sci. 118, 3573-3584.
Moustakas, A., and Heldin, C.H. (2009). The regulation of TGFβ signal transduction. Development 136, 3699-3714.
Mu, Y., Gudey, S.K., and Landstrom, M. (2012). Non-Smad signaling pathways. Cell Tissue Res. 347, 11-20.
Ouwens, D.M., de Ruiter, N.D., van der Zon, G.C., Carter, A.P., Schouten, J., van der Burgt, C., Kooistra, K., Bos, J.L., Maassen, J.A., and van Dam, H. (2002). Growth factors can activate ATF2 via a two-step mechanism: phosphorylation of Thr71 through the Ras-MEK-ERK pathway and of Thr69 through RalGDS-Src-p38. 21, 3782-3793.
Owens, G.K., Kumar, M.S., and Wamhoff, B.R. (2004). Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol. Rev. 84, 767-801.
Papadimitriou, E., Kardassis, D., Moustakas, A., and Stournaras, C. (2011). TGFβ-induced early activation of the small GTPase RhoA is Smad2/3-independent and involves Src and the guanine nucleotide exchange factor Vav2. Cell. Physiol. Biochem. 28, 229-238.
Pardali, E., and ten Dijke, P. (2012). TGFβ signaling and cardiovascular diseases. Int. J. Biol. Sci. 8, 195-213.
Pidkovka, N.A., Cherepanova, O.A., Yoshida, T., Alexander, M.R., Deaton, R.A., Thomas, J.A., Leitinger, N., and Owens, G.K. (2007). Oxidized phospholipids induce phenotypic switching of vascular smooth muscle cells in vivo and in vitro. Circ. Res. 101, 792-801.
Pomies, P., Louis, H.A., and Beckerle, M.C. (1997). CRP1, a LIM domain protein implicated in muscle differentiation, interacts with α-actinin. J. Cell Biol. 139, 157-168.
Raines, E.W., and Ferri, N. (2005). Thematic review series: The immune system and atherogenesis. Cytokines affecting endothelial and smooth muscle cells in vascular disease. J. Lipid Res. 46, 1081-1092.
Ross, R. (1993). The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362, 801-809.
Ross, R. (1999). Atherosclerosis-an inflammatory disease. N. Engl. J. Med. 340, 115-126.
Sano, Y., Harada, J., Tashiro, S., Gotoh-Mandeville, R., Maekawa, T., and Ishii, S. (1999). ATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-β signaling. J. Biol. Chem. 274, 8949-8957.
Sato, M., Kawai-Kowase, K., Sato, H., Oyama, Y., Kanai, H., Ohyama, Y., Suga, T., Maeno, T., Aoki, Y., Tamura, J., et al. (2005). c-Src and hydrogen peroxide mediate transforming growth factor-β1-induced smooth muscle cell-gene expression in 10T1/2 cells. Arterioscler. Thromb. Vasc. Biol. 25, 341-347.
Sekelsky, J.J., Newfeld, S.J., Raftery, L.A., Chartoff, E.H., and Gelbart, W.M. (1995). Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347-1358.
Shi, Y., and Massagué, J. (2003). Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus. Cell 113, 685-700.
Shinohara, S., Shinohara, S., Kihara, T., and Miyake, J. (2012). Regulation of Differentiated Phenotypes of Vascular Smooth Muscle Cells.
Siegel, P.M., and Massague, J. (2003). Cytostatic and apoptotic actions of TGF-β in homeostasis and cancer. Nat. Rev. Cancer 3, 807-821.
Siegel, P.M., Shu, W., Cardiff, R.D., Muller, W.J., and Massague, J. (2003). Transforming growth factor β signaling impairs Neu-induced mammary tumorigenesis while promoting pulmonary metastasis. Proc. Natl. Acad. Sci. U. S. A. 100, 8430-8435.
Sorrentino, A., Thakur, N., Grimsby, S., Marcusson, A., von Bulow, V., Schuster, N., Zhang, S., Heldin, C.H., and Landstrom, M. (2008). The type I TGF-β receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner. Nat. Cell Biol. 10, 1199-1207.
Steinmuller, L., and Thiel, G. (2003). Regulation of gene transcription by a constitutively active mutant of activating transcription factor 2 (ATF2). Biol. Chem. 384, 667-672
Tedgui, A., and Mallat, Z. (2006). Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol. Rev. 86, 515-581.
ten Dijke, P. and Arthur, H.M. (2007). Extracellular control of TGFβ signaling in vascular development and disease. Nat. Rev. Mol. Cell Biol. 8, 857-869.
Thyberg, J., Palmberg, L., Nilsson, J., Ksiazek, T., and Sjolund, M. (1983). Phenotype modulation in primary cultures of arterial smooth muscle cells. On the role of platelet-derived growth factor. Differentiation 25, 156-167.
Vlahopoulos, S.A., Logotheti, S., Mikas, D., Giarika, A., Gorgoulis, V., and Zoumpourlis, V. (2008). The role of ATF-2 in oncogenesis. Bioessays 30, 314-327.
Wang, Z., Wang, D.Z., Hockemeyer, D., McAnally, J., Nordheim, A., and Olson, E.N. (2004). Myocardin and ternary complex factors compete for SRF to control smooth muscle gene expression. Nature 428, 185-189.
Wei, J., Gorman, T.E., Liu, X., Ith, B., Tseng, A., Chen, Z., Simon, D.I., Layne, M.D., and Yet, S.F. (2005). Increased neointima formation in cysteine-rich protein 2-deficient mice in response to vascular injury. Circ. Res. 97, 1323-1331.
Weiskirchen, R., and Gunther, K. (2003). The CRP/MLP/TLP family of LIM domain proteins: acting by connecting. Bioessays 25, 152-162.
Wygrecka, M., Zakrzewicz, D., Taborski, B., Didiasova, M., Kwapiszewska, G., Preissner, K.T., and Markart, P. (2012). TGF-β1 induces tissue factor expression in human lung fibroblasts in a PI3K/JNK/Akt-dependent and AP-1-dependent manner. Am. J. Respir. Cell Mol. Biol. 47, 614-627.
Yamamoto, K., Morishita, R., Tomita, N., Shimozato, T., Nakagami, H., Kikuchi, A., Aoki, M., Higaki, J., Kaneda, Y., and Ogihara, T. (2000). Ribozyme oligonucleotides against transforming growth factor-β inhibited neointimal formation after vascular injury in rat model: potential application of ribozyme strategy to treat cardiovascular disease. Circulation 102, 1308-1314.
Yamashita, M., Fatyol, K., Jin, C., Wang, X., Liu, Z., and Zhang, Y.E. (2008). TRAF6 Mediates Smad-Independent Activation of JNK and p38 by TGF-β. Mol. Cell 31, 918-924.
Yokote, K., Kobayashi, K., and Saito, Y. (2006). The role of Smad3-dependent TGF-β signal in vascular response to injury. Trends Cardiovasc. Med. 16, 240-245.
Yoshida, T., Gan, Q., and Owens, G.K. (2008). Kruppel-like factor 4, Elk-1, and histone deacetylases cooperatively suppress smooth muscle cell differentiation markers in response to oxidized phospholipids. Am. J. Physiol. Cell Physiol. 295, C1175-C1182.
Zawel, L., Dai, J.L., Buckhaults, P., Zhou, S., Kinzler, K.W., Vogelstein, B., and Kern, S.E. (1998). Human Smad3 and Smad4 are sequence-specific transcription activators. Mol. Cell 1, 611-617.
Zhang, Y.E. (2009). Non-Smad pathways in TGF-β signaling. Cell Res. 19, 128-139.
Zimmerman, M.A., Reznikov, L.L., Raeburn, C.D., and Selzman, C.H. (2004). Interleukin-10 attenuates the response to vascular injury. J. Surg. Res. 121, 206-213.