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 SOX9
Homo sapiens
 HIF1A
Homo sapiens
 Pax6
Mus musculus
 PAX6
Homo sapiens
 Snai2
Mus musculus
 PPARA
Homo sapiens
 Ppara
Mus musculus
 Thrb
Mus musculus
 SNAI2
Homo sapiens
 Tbr1
Mus musculus
Transcription Factor Encyclopedia  BETA
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Overview

Twist was identified as a zygotic gene involved in early mesodermal patterning in Drosophila [1]. Drosophila Twist mutants fail to gastrulate indicating its importance in regulating morphogenetic movements during gastrulation . Following gastrulation, Twist plays an important role in Drosophila myogenesis [2]. In mice, Twist homozygous null mutant embryos die at E10.5 indicating a requirement for Twist in the development of the head mesenchyme, somites and limb buds but not for gastrulation [3][4]. Although heterozygous mutant mice are viable, they exhibit skull defects of poorly developed squamosal bones and of overdeveloped interparietal bones as well as limb abnormalities [5]. In humans, Twist homozygous null mutant embryos are not viable, while heterozygous loss of Twist results in the autosomal dominant Saethre-Chotzen syndrome which is characterized by craniosynostosis, facial dimorphisms and hand and foot abnormalities [6][7]. To date, more than 70 Twist mutants have been found in patients with Saethre-Chotzen syndrome [8]. Most mutations affect the bHLH domain and abrogate dimerization or abolish DNA binding. In addition, mutations in the helix domain of the Twist gene can cause subcellular mislocalization and increased degradation of its protein product, which results in the repression of pro-inflammatory cytokine gene expression [9][10]. Besides its well-known role in development, Twist is also involved in programmed cell death. Twist haploinsufficiency in Saethre-Chotzen syndrome induces calvarial osteoblast apoptosis while homozygous null mutants cause apoptosis during mice development [3]. Twist also interferes with the ARF-p53 regulation pathway blocking c-myc induced apoptosis in mouse embryo fibroblasts [11]. Twist is essential in cell fate specification, tissue differentiation and growth regulation [12][13][14][15].

Recent evidence indicates that Twist can be involved with several pathways that lead to the formation of cancer by halting differentiation, controlling apoptosis by interfering with the p53 tumor suppressor pathway and inducing an epithelial to mesenchymal transition. Over-expression of Twist in rhabdomyosarcomas inhibits apoptosis and interferes with p53 tumor suppression [11][16]. Twist over-expression is found in over 50% of rhabdomyosarcomas and 40% of gastric carcinomas [11][17]. Up-regulation of Twist is found associated with melanoma and T-cell lymphoma [18][19]. Twist has also been shown to be up-regulated in prostate cancer [20]. Increased expression of Twist in four tumor cell lines (nasopharyngeal, bladder, ovarian, and prostate) was found to be associated with resistance to taxol as well as other drugs that disrupt microtubules [21]. Twist is also overexpressed in over 50% of breast cancers [22]. Moreover, over-expression of Twist causes an epithelial to mesenchymal transition (EMT) both in mouse and human breast cancer cell lines [22][23]. The cellular transformations that modulate these capabilities appear to be analogous to some of the cellular changes that are required for normal embryonic development. Some of these changes are associated with turning off of genes coding for cell adhesion molecules such as E-cadherin [24], or initiating synthesis of extracellular matrix molecules like fibronectin and proteolytic enzymes involved in matrix degradation that contribute to cell motility and invasiveness [25][26].

References
  1. Thisse B et al. The twist gene: isolation of a Drosophila zygotic gene necessary for the establishment of dorsoventral pattern. Nucleic Acids Res., 15(8):3439-53. (PMID 3106932)
  2. Baylies MK and Bate M. twist: a myogenic switch in Drosophila. Science, 272(5267):1481-4. (PMID 8633240)
  3. Chen ZF and Behringer RR. twist is required in head mesenchyme for cranial neural tube morphogenesis. Genes Dev., 9(6):686-99. (PMID 7729687)
  4. O'Rourke MP and Tam PP. Twist functions in mouse development. Int. J. Dev. Biol., 46(4):401-13. (PMID 12141426)
  5. Bourgeois P et al. The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome. Hum. Mol. Genet., 7(6):945-57. (PMID 9580658)
  6. el Ghouzzi V et al. Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat. Genet., 15(1):42-6. (PMID 8988167)
  7. Howard TD et al. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome. Nat. Genet., 15(1):36-41. (PMID 8988166)
  8. Gripp KW et al. Mutations in the human TWIST gene. Hum. Mutat., 15(2):150-5. (PMID 10649491)
  9. El Ghouzzi V et al. Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location. Hum. Mol. Genet., 9(5):813-9. (PMID 10749989)
  10. Sosić D et al. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-kappaB activity. Cell, 112(2):169-80. (PMID 12553906)
  11. Maestro R et al. Twist is a potential oncogene that inhibits apoptosis. Genes Dev., 13(17):2207-17. (PMID 10485844)
  12. Spicer DB et al. Inhibition of myogenic bHLH and MEF2 transcription factors by the bHLH protein Twist. Science, 272(5267):1476-80. (PMID 8633239)
  13. Gitelman I. Twist protein in mouse embryogenesis. Dev. Biol., 189(2):205-14. (PMID 9299114)
  1. Technau U and Scholz CB. Origin and evolution of endoderm and mesoderm. Int. J. Dev. Biol., 47(7-8):531-9. (PMID 14756329)
  2. Lee MS et al. TWIST, a basic helix-loop-helix transcription factor, can regulate the human osteogenic lineage. J. Cell. Biochem., 75(4):566-77. (PMID 10572240)
  3. Stasinopoulos IA et al. HOXA5-twist interaction alters p53 homeostasis in breast cancer cells. J. Biol. Chem., 280(3):2294-9. (PMID 15545268)
  4. Rosivatz E et al. Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. Am. J. Pathol., 161(5):1881-91. (PMID 12414534)
  5. Hoek K et al. Expression profiling reveals novel pathways in the transformation of melanocytes to melanomas. Cancer Res., 64(15):5270-82. (PMID 15289333)
  6. van Doorn R et al. Aberrant expression of the tyrosine kinase receptor EphA4 and the transcription factor twist in Sézary syndrome identified by gene expression analysis. Cancer Res., 64(16):5578-86. (PMID 15313894)
  7. Kwok WK et al. Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Res., 65(12):5153-62. (PMID 15958559)
  8. Wang X et al. Identification of a novel function of TWIST, a bHLH protein, in the development of acquired taxol resistance in human cancer cells. Oncogene, 23(2):474-82. (PMID 14724576)
  9. Yang J et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117(7):927-39. (PMID 15210113)
  10. Mironchik Y et al. Twist overexpression induces in vivo angiogenesis and correlates with chromosomal instability in breast cancer. Cancer Res., 65(23):10801-9. (PMID 16322226)
  11. Vesuna F et al. Twist is a transcriptional repressor of E-cadherin gene expression in breast cancer. Biochem. Biophys. Res. Commun., 367(2):235-41. (PMID 18062917)
  12. Cano A et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat. Cell Biol., 2(2):76-83. (PMID 10655586)
  13. Woodhouse EC et al. General mechanisms of metastasis. Cancer, 80(8 Suppl):1529-37. (PMID 9362419)
Figures
FIGURE 1 TWIST1 domains
A. Depiction of TWIST1 functional domains. B. A cartoon depiction of TWIST1 dimer binding to DNA.
This figure was created by the authors of this article. The authors of this article have provided the assurance that this figure constitutes their original work.