twist is a potential oncogene that inhibits apoptosis

Abstract

Oncogene activation increases susceptibility to apoptosis. Thus, tumorigenesis must depend, in part, on compensating mutations that protect from programmed cell death. A functional screen for cDNAs that could counteract the proapoptotic effects of the myc oncogene identified two related bHLH family members, Twist and Dermo1. Both of these proteins inhibited oncogene-and p53-dependent cell death. Twist expression bypassed p53-induced growth arrest. These effects correlated with an ability of Twist to interfere with activation of a p53-dependent reporter and to impair induction of p53 target genes in response to DNA damage. An underlying explanation for this observation may be provided by the ability of Twist to reduce expression of the ARF tumor suppressor. Thus, Twist may affect p53 indirectly through modulation of the ARF/MDM2/p53 pathway. Consistent with a role as a potential oncoprotein, Twist expression promoted colony formation of E1A/ras-transformed mouse embryo fibroblasts (MEFs) in soft agar. Furthermore, Twist was inappropriately expressed in 50% of rhabdomyosarcomas, a tumor that arises from skeletal muscle precursors that fail to differentiate. Twist is known to block myogenic differentiation. Thus, Twist may play multiple roles in the formation of rhabdomyosarcomas, halting terminal differentiation, inhibiting apoptosis, and interfering with the p53 tumor-suppressor pathway.

Frequent genomic abnormalities at TWIST in human pediatric osteosarcomas

“…14,36,37 Only 9 samples present an amplification of the gene, which is expected to result in higher amounts of gene products in malignant bone tissues, according to previous studies. 18,22 These results pointed also toward frequent heterozygous deletions at TWIST in the DNA of pediatric osteosarcomas.…”

“…[9][10][11] In contrast, abnormal activation of TWIST has been implicated in several human cancers, as in gastric cancer 12 and nephroblastoma. 13 In addition, TWIST was shown to play a role in the formation of rhabdomyosarcoma by inhibiting apoptotis 14 and also by halting terminal differentiation of muscle cells 14 and mammary gland. 15 Furthermore, recent reports related that the activation of TWIST is linked to the epithelial-to-mesenchymal switch and promotes tumor cell metastasis from soft tissues.…”

The TWIST1 oncogene is a direct target of hypoxia-inducible factor-2α

“…Expression of TWIST1 has been shown to induce metastatic capacity and antiapoptotic activity of human cancer cells (Maestro et al, 1999;Yang et al, 2004). Hypoxia has been implicated in similar processes ).…”

“…Loss of TWIST1 expression is associated with the hereditary SaethreChotzen syndrome that is characterized by inappropriate fibroblast growth factor receptor 2 (FGFR2) expression (Wilkie and Morriss-Kay, 2001). TWIST1 acts as an inhibitor of N-MYC-induced apoptosis, establishing TWIST1 as an oncogene (Maestro et al, 1999). In human breast cancers, high TWIST1 levels correlate with invasive lobular carcinoma, a highly infiltrating tumor type associated with loss of E-cadherin expression and required for breast cancer metastases in a murine model for breast cancer (Yang et al, 2004).…”

Translational control of TWIST1 expression in MCF-10A cell lines recapitulating breast cancer progression

“…TWIST1 has a major role during development in mammals and is an important factor in tumorigenesis. 1 It contributes to metastasis by promoting epithelial --mesenchymal transition (EMT), 2 and is misregulated in a variety of human cancers. 3 TWIST1 is regulated both transcriptionally and post-transcriptionally.…”