HOXA5-twist interaction alters p53 homeostasis in breast cancer cells.
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The homeotic gene HOXA5 has been shown to play an important role in breast tumorigenesis. We have shown that loss of p53 correlated with loss of a developmentally regulated transcription factor, HOXA5, in primary breast cancer. Searching for potential protein interacting partners we found that HOXA5 binds to an anti-apoptotic protein, Twist. Furthermore, Twist-overexpressing MCF-7 cells displayed a deregulated p53 response to gamma-radiation and decreased regulation of downstream target genes. Using a p53-promoter-reporter system, we demonstrated that HOXA5 could partially restore the inhibitory effects of Twist on p53 target genes. These effects are likely mediated through both the transcriptional up-regulation of p53 and the protein-protein interaction between HOXA5 and Twist. Thus, the loss of HOXA5 expression could lead to the functional activation of Twist resulting in aberrant cell cycle regulation and promoting breast carcinogenesis. (+info)
cDermo-1 misexpression induces dense dermis, feathers, and scales.
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Reciprocal epithelio-mesenchymal interactions between the prospective epidermis and the underlying dermis are the major driving forces in the development of skin appendages. Feather development is initiated by a still unknown signal from the dermis in feather-forming skin. The morphological response of the ectoderm to this signal is the formation of an epidermal placode, which signals back to the mesenchyme to induce dermal condensations. Together, epidermal and dermal components constitute the outgrowing feather bud. The bHLH transcription factor cDermo-1 is expressed in developing dermis and is the earliest known marker of prospective feather tracts. To test its function during feather development, we forced cDermo-1 expression in embryonic chicken dermis using a retroviral expression vector. In featherless (apteric) regions, cDermo-1 misexpression induced dense, thickened dermis normally observed in feathered skin (pterylae), and leads to the development of regularly spaced and normally shaped ectopic feather buds. In pterylae, cDermo-1 misexpression enhanced feather growth. In hindlimb skin, according to the local skin identity, misexpression of cDermo-1 induced ectopic scale formation. Thus, we show that forced cDermo-1 expression in developing dermis is sufficient to launch the developmental program leading to skin appendage formation. We propose a role of cDermo-1 at the initial stages of feather induction upstream of FGF10. (+info)
Oncogenic cooperation between H-Twist and N-Myc overrides failsafe programs in cancer cells.
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N-Myc oncogene amplification is a frequent event in neuroblastoma and is strongly correlated with advanced disease stage and treatment failure. Similarly to c-Myc oncogenic activation, N-Myc deregulation promotes both cell proliferation and p53-dependent apoptosis by sensitizing cells to a variety of insults. Intriguingly, p53 mutations are uncommon in neuroblastomas, strongly suggesting that an alternative cooperating event circumvents this safeguard against oncogene-driven neoplasia. By performing a pangenomic cDNA microarray analysis, we demonstrate that human Twist is constantly overexpressed in N-Myc-amplified neuroblastomas. H-Twist overexpression is responsible for the inhibition of the ARF/p53 pathway involved in the Myc-dependent apoptotic response. This oncogenic cooperation of two key regulators of embryogenesis causes cell transformation and malignant outgrowth. (+info)
Twist induces an epithelial-mesenchymal transition to facilitate tumor metastasis.
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Tumor metastasis-the spreading of primary tumor cells to distal organs - is the major cause of death of cancer patients. The metastatic process consists of four distinct steps, invasion, intravasation, extravasation, and metastatic growth, and primary tumor cells need to acquire different genetic characteristics to accomplish each step. The main players during the metastatic process remain, however, largely unknown. A recent report in Cell by Robert Weinberg's group (Yang et al., Cell 2004;117:927-39) adds the transcription factor Twist to the list of metastatis regulators. Suppression of Twist expression in tumor cells inhibits the metastatic potential, whereas its overexpression induces an epithelial-mesenchymal transition (EMT) in epithelial cells. This study provides direct evidence that EMT may be an essential process during metastasis and should appropriately stimulate further investigations of EMT in many laboratories. (+info)
Loss of imprinting of Igf2 alters intestinal maturation and tumorigenesis in mice.
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Loss of imprinting (LOI) of the insulin-like growth factor II gene (IGF2) is an epigenetic alteration that results in a modest increase in IGF2 expression, and it is present in the normal colonic mucosa of about 30% of patients with colorectal cancer. To investigate its role in intestinal tumorigenesis, we created a mouse model of Igf2 LOI by crossing female H19+/- mice with male Apc+/Min mice. Mice with LOI developed twice as many intestinal tumors as did control littermates. Notably, these mice also showed a shift toward a less differentiated normal intestinal epithelium, reflected by an increase in crypt length and increased staining with progenitor cell markers. A similar shift in differentiation was seen in the normal colonic mucosa of humans with LOI. Thus, altered maturation of nonneoplastic tissue may be one mechanism by which epigenetic changes affect cancer risk. (+info)
Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities.
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Autosomal dominant mutations in the gene encoding the basic helix-loop-helix transcription factor Twist1 are associated with limb and craniofacial defects in humans with Saethre-Chotzen syndrome. The molecular mechanism underlying these phenotypes is poorly understood. We show that ectopic expression of the related basic helix-loop-helix factor Hand2 phenocopies Twist1 loss of function in the limb and that the two factors have a gene dosage-dependent antagonistic interaction. Dimerization partner choice by Twist1 and Hand2 can be modulated by protein kinase A- and protein phosphatase 2A-regulated phosphorylation of conserved helix I residues. Notably, multiple Twist1 mutations associated with Saethre-Chotzen syndrome alter protein kinase A-mediated phosphorylation of Twist1, suggesting that misregulation of Twist1 dimerization through either stoichiometric or post-translational mechanisms underlies phenotypes of individuals with Saethre-Chotzen syndrome. (+info)
Expression of twist and wnt in human breast cancer.
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Twist, a transcription factor of the basic helix-loop-helix class, has been suggested to have oncogenic properties. We reported Twist expression was regulated by Wnt/beta-catenin signaling and that both Wnt-1 and Twist could contribute to mammary tumorigenesis. The aim of this study was to demonstrate the expression of Twist, Wnt-1 and Wnt-2 in human breast cancer tissue. We examined the expression in patients with breast cancer by RT-PCR and immunohistochemistry. RT-PCR of twenty-three pairs of cancer and normal breast tissue revealed that Twist was up-regulated in 69.6% (16/23) of the cancer lesions and 21.7% (5/23) of the normal breast tissues. Wnt-2 was up-regulated in all of the cancer lesions and 13.0% (3/23) of the normal breast tissues, whereas Wnt-1 was expressed in both the cancer and normal breast tissues of the five cases examined. Immunohistochemical analyses revealed that Twist was positively expressed in 52.2% (12/23) of the cancer lesions and 34.8% (8/23) of the normal breast tissues. Twist and Wnt-2 are highly expressed in breast cancer tissue, suggesting that both molecules could play important roles in mammary carcinogenesis. (+info)
Quantitative analysis of binding motifs mediating diverse spatial readouts of the Dorsal gradient in the Drosophila embryo.
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Dorsal is a sequence-specific transcription factor that is distributed in a broad nuclear gradient across the dorsal-ventral (DV) axis of the early Drosophila embryo. It initiates gastrulation by regulating at least 30-50 target genes in a concentration-dependent fashion. Previous studies identified 18 enhancers that are directly regulated by different concentrations of Dorsal. Here, we employ computational methods to determine the basis for these distinct transcriptional outputs. Orthologous enhancers were identified in a variety of divergent Drosophila species, and their comparison revealed several conserved sequence features responsible for DV patterning. In particular, the quality of Dorsal and Twist recognition sequences correlates with the DV coordinates of gene expression relative to the Dorsal gradient. These findings are entirely consistent with a gradient threshold model for DV patterning, whereby the quality of individual Dorsal binding sites determines in vivo occupancy of target enhancers by the Dorsal gradient. Linked Dorsal and Twist binding sites constitute a conserved composite element in certain "type 2" Dorsal target enhancers, which direct gene expression in ventral regions of the neurogenic ectoderm in response to intermediate levels of the Dorsal gradient. Similar motif arrangements were identified in orthologous loci in the distant mosquito genome, Anopheles gambiae. We discuss how Dorsal and Twist work either additively or synergistically to activate different target enhancers. (+info)