TWIST1 (twist homolog 1 (Drosophila))

Description	The 20.9 kDa protein encoded by TWIST1 gene is a highly conserved transcription factor that belongs to the family of basic helix-loop-helix (bHLH) proteins. In vertebrates, it is involved in embryonic development through the regulation of epithelial-mesenchymal transitions (EMT) during neural crest migration, also it regulates mesoderm determination, myogenesis, and morphogenesis (Hebrok et al., 1994; Chen et al., 1995). Additionally, TWIST1 is involved in the negative regulation of cellular determination and in the differentiation of several lineages including myogenesis, osteogenesis (Bialek et al., 2004), and neurogenesis (Soo et al., 2002). Inhibits myogenesis by sequestrating E proteins, avoiding trans-activation by MEF2, and inhibiting DNA-binding by MYOD1 through physical interaction. Also represses expression of proinflammatory cytokines such as TNFA and IL1B (Barnes et al., 2009). Mutations in this gene have been found in patients with Saethre-Chotzen syndrome (Howard et al., 1997). TWIST1 has been suggested to be oncogenic, contributing to metastasis through its involvement in EMT regulation (Yang et al., 2004). In addition, TWIST1 is overexpressed in multiple tumor types, and it is usually associated with poor prognosis. In mammals, there are two Twist-like proteins, TWIST1 and TWIST2 that share high structural homology (Li et al., 1995; Wolf et al., 1991). It is thought that during osteoblast development TWIST2 or Dermo1 may inhibit osteoblast maturation and maintain cells in a preosteoblast phenotype [provided by RefSeq]. Interestingly, TWIST2 has a pro-oncogenic role in human cancer (Ansieau et al., 2008). Structure TWIST1 protein contains a helix-loop-helix DNA-binding domain. Efficient DNA binding requires dimerization with another bHLH protein.
	(Mod Base provided)
Expression	The strongest expression of the mRNA is in placental tissue. In adults, mesoderm-derived tissues express TWIST1 mRNA preferentially.
Localisation	Nucleus.
Function	Role in embryonic development The Twist gene was originally identified as being required for mesoderm induction in Drosophila (Thisse et al., 1987; Leptin et al., 1990) which expression is induced by an interleukin-1-like TOLL receptor through nuclear factor kappaB activation (Furlong et al., 2001). In vertebrates, Twist is predominantly expressed in neural crest cell where is essential for correct patterning of the neural tube (Chen and Behringer, 1995; Soo et al., 2002). However, the nuclear factor kappaB pathway is not involved in mesoderm formation or neural crest development in vertebrates. Instead, BMP-, Wnt-, and fibroblast growth factor-activated pathways are known to modulate vertebrate neural crest development (Meulemans et al., 2004). During mesoderm formation in Drosophila, Twist induces the expression of the transcription factor Snail to allow invagination and mesoderm differentiation (Leptin and Grunewald, 1990). During neural crest development in vertebrates, expression of Snail and Slug occurs at the neural plate border where Twist is also expressed, and all three transcription factors play critical roles in neural crest formation (Meulemans and Bronner-Fraser, 2004). Additional evidence supports the key role of Twist in development, since Twist mutation in mice causes failure in cranial neural tube closure, indicating its role in proper migration and differentiation of neural crest and head mesenchymal cells (Chen and Behringer, 1995; Soo et al., 2002). Role in myogenesis TWIST1 functionally inhibits muscle development by sequestrating E proteins from forming functional myogenic complexes with the skeletal muscle specific bHLH factor, MyoD. The mechanism of action is through the block of both cis- and trans- MyoD elements, and inhibiting transactivation of Mef2 (Barnes and Firulli, 2009). Role in EMT EMT is a process whereby epithelial cell layers lose polarity and cell-cell contacts and undergo a dramatic remodelling of the cytoskeleton. EMT is essential for the morphogenic movements underlying gastrulation and the subsequent formation of various tissues and organs such as the neural crest, heart, musculoskeletal system, craniofacial structures, and peripheral nervous system, and is also implicated in tissue repair in the adult. TWIST1 induces EMT through repression of E-cadherin (Yang et al., 2004). Cells undergoing EMT acquire expression of mesenchymal components and manifest a migratory phenotype. TWIST1 triggers the acquisition of invasive properties through induction of pro-migratory molecules, such as the cell adhesion protein N-cadherin (Alexander et al., 2006) and RhoC, as consequence of inducing the microRNA molecule miR-10b (Ma et al., 2007). Role in control of apoptosis Twist, as a basic helix-loop-helix transcription factor, may activate or suppress diverse downstream targets, including apoptosis genes. Two studies reported that the expression of Twist could inhibit Myc-induced apoptosis in mouse embryo fibroblasts (Maestro et al., 1999) and neuroblastoma cells (Valsesia-Wittmann et al., 2004). This transcriptional control is relevant during EMT, since Twist may need to activate antiapoptotic programs in order to allow epithelial cells to convert to a mesenchymal fate while avoiding cell death due to loss of cell-cell adhesions by epithelial cells. Role in cancer TWIST1 has a key role during cancer development and progression in multiple tumour types. There are four main different malignant processes where this transcription factor is involved: EMT (Vernon et al., 2004), resistance to apoptosis by cytotoxic drugs (Wang et al., 2004) and pro-survival signalling (Puisieux et al., 2006) and hypoxia (Yang et al., 2008).

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