3 E). the EMT and profibrotic responses to TGF-. Thus, JunB represents an important target in diseases associated with EMT, including cancer and fibrosis. Introduction The process of epithelialCmesenchymal transition (EMT) is usually implicated in malignancy progression, wound healing, and tissue fibrosis as well as normal embryonic development (Kalluri and Neilson, 2003; Thiery, 2003; Lee et al., 2006). In tissue fibrosis and wound healing, EMT is thought to contribute to generation of myofibroblasts and myofibroblast-like cells that mediate deposition of ECM proteins, such as collagens and fibronectin. In cancer, EMT prospects to generation of more aggressive and invasive carcinoma cells as well as malignancy stem cells. EMT entails disassembly of the polarized epithelial architecture and remodeling of the cell cytoskeleton, including intermediate and actin filaments. TGF- cytokines have emerged as major regulators of EMT in human diseases and embryonic development (Zavadil and B?ttinger, 2005). TGF- can induce EMT in normal and carcinoma cells, disrupting cell junctions and inducing actin fibers linked to focal adhesions (Miettinen et al., 1994; Fialka et al., 1996; Oft et al., 1996; Piek et al., 1999; Bakin et al., 2004; Brown et al., 2004). Under physiological conditions, TGF- functions as a potent tumor suppressor, regulating normal tissue homeostasis, cell proliferation, and matrix deposition (Stover et al., 2007). Malignant cancers A-381393 are unresponsive to antimitogenic effects of TGF- and produce elevated levels of TGF- (Walker and Dearing, 1992; Wikstr?m et al., 1998; Maehara et al., 1999). This has been linked to the induction of EMT in carcinoma cells, promoting tumor invasion, resistance to therapy, and metastatic spread (Maehara et al., 1999; Huber et al., 2005; Lee et al., 2006; Stover et al., 2007). The mechanisms underlying TGF-Cinduced EMT and fibrotic responses are not fully comprehended. TGF- cytokines are deposited in the matrix in a latent/inactive form and are released in active form by numerous environmental signals (Annes et al., 2003). Active TGF- binds to the receptor complex and stimulates a set of signaling events, leading to changes in gene expression and cell behavior (Pardali and Moustakas, 2007). The EMT response to TGF- requires transcription and de novo protein synthesis (Bakin et al., 2004). Smad transcription factors, PI3 kinase, and MAPKs p38 and ERK have been implicated in EMT (Zavadil and B?ttinger, 2005). Receptor-associated Smad3 and Smad4 play a major role in the EMT response (Bakin et al., 2004; Levy and Hill, 2005; Valcourt et al., 2005). Small GTPases Rac1 and RhoA contribute to EMT by activating p38 MAPK, PI3K-Akt, and Rho kinase signaling (Bakin et al., 2000, 2002; Bhowmick et al., 2001; Zavadil and B?ttinger, 2005). Recent studies suggest that TGF-Cinduced EMT entails Smad-dependent down-regulation of inhibitor of differentiation 2/3 (Id2/3) helix-loop-helix Rabbit Polyclonal to Bak transcription factors A-381393 (Kondo et al., 2004; Kowanetz et al., 2004). In some cell systems, TGF- up-regulates Twist, Snail, Slug, and Hmga2 (Moustakas and Heldin, 2007). Forced expression of Hmga2, Snail, or Twist alone can induce EMT, down-regulating E-cadherin and increasing cell migration (Moustakas and Heldin, 2007). Formation of actin stress fibers is a main characteristic of TGF-Cinduced EMT. Smads regulate expression of proteins, mediating the formation of actin fibers A-381393 (tropomyosin Tpm1, -actinin Actn1, and calponin Cnn2) and focal adhesions, including palladin and integrins (Bakin et al., 2004; Valcourt et al., 2005; Zheng et al., 2008; Safina et al., 2009; Bianchi et al., 2010). Tropomyosin-mediated actin fibers control tumor cell invasion A-381393 and anchorage-independent growth (Pawlak and Helfman, 2001; Zheng et al., 2008; Safina et al., 2009). Actin fibers and focal adhesions are also actively involved in the deposition and remodeling of the ECM and may facilitate tissue fibrosis. Activating protein 1 (AP1) transcription factors contribute to numerous TGF- biological responses (Moustakas and Heldin, 2007). The AP1 factors are dimeric complexes of the basic leucine zipper proteins representing the FOS, JUN, activating transcription factor (ATF)/cAMP response element-binding, or musculoaponeurotic fibrosarcoma families (Eferl and Wagner, 2003). The leucine zipper domain name mediates hetero- and homodimerization of these proteins, whereas the basic regions are responsible for DNA binding. Fos and Jun can induce EMT and promote invasion in epithelial cell lines (Ozanne et al., 2007), disrupting epithelial cell polarity without down-regulation of E-cadherin (Fialka et al., 1996). Similarly, constitutive MEK1-JUN signaling dissolves cellCcell junctions but does not suppress E-cadherin (Pinkas and Leder, 2002). Jun and JunB share considerable homology within the leucine zipper and basic domains, and JunB can rescue a lethal phenotype in Jun-null mice (Passegu et al., 2002). Despite their homology, these proteins display different transcriptional activity. Jun is usually a strong transcriptional activator, whereas JunB is usually a modest trans-activator and may even A-381393 repress transcription (Finch et al., 2002; Eferl and Wagner, 2003)..