Disease relevance of ZEB1

• E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations [1].
• The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas [2].
• Family reports of inguinal hernia, hydrocele, and possible bone anomalies in affected individuals suggest that individuals with TCF8 mutations should be examined for nonocular anomalies [3].
• Cyclooxygenase-2-dependent regulation of E-cadherin: prostaglandin E(2) induces transcriptional repressors ZEB1 and snail in non-small cell lung cancer [4].
• The presence of an intronic deletion in p73 and high levels of ZEB1 alter the TAp73/DeltaTAp73 ratio in colorectal carcinomas [5].

High impact information on ZEB1

• Targeting ZEB1 might be a promising therapeutic option to prevent metastasis [6].
• Mutations in TCF8 cause posterior polymorphous corneal dystrophy and ectopic expression of COL4A3 by corneal endothelial cells [3].
• We previously mapped PPCD to a region (PPCD3) on chromosome 10 containing the gene that encodes the two-handed zinc-finger homeodomain transcription factor TCF8 [3].
• Additionally, ZEB-2 inhibits a wider spectrum of transcription factors than ZEB-1 [7].
• Mutation of the ZEB-1 gene led to a severe T cell phenotype and skeletal defects but, interestingly, no defects were evident in other ZEB-1-expressing tissues [7].

Biological context of ZEB1

• The TCF8 gene encodes a zinc finger protein (Nil-2-a) [8].
• Southern hybridization and somatic cell hybrids are used to demonstrate that the murine and human genomes contain related genes for Nil-2-a. TCF8 resides on human chromosome 10 [8].
• However, there are also differences between ZEB-1 and ZEB-2, both in activity and tissue distribution [7].
• To gain insights into the molecular mechanism by which AREB6 activates and represses gene expression, we analyzed the domain structure of AREB6 in the context of a heterologous DNA-binding domain by transient-transfection assays [9].
• In transient transfection assays, p65 increased ZEB-1 promoter activity [10].

Anatomical context of ZEB1

• Snail overexpression in several cell lines raised ZEB1 RNA levels and increased the activity of ZEB1 promoter [11].
• However, since ZEB1 expression persisted after Snail was down-regulated, ZEB1 may regulate epithelial genes in several tumor cell lines [11].
• Whereas ZEB-1 and ZEB-2 overlap in skeletal muscle and CNS (providing an explanation for why mutation of ZEB-1 alone has little effect in these tissues), they show a different pattern of expression in lymphoid cells [7].
• ZEB-1, but not ZEB-2, is expressed in T cells from the thymus ZEB-2 appears to be expressed on splenic B cells [7].
• NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2 [10].

Associations of ZEB1 with chemical compounds

• We identified a significant correlation between sensitivity to gefitinib and expression of E-cadherin, and ZEB1, suggesting their predictive value for responsiveness to EGFR-tyrosine kinase inhibitors [12].
• ZEB1 protein is up-regulated in the myometrium and endometrial stroma after progesterone or estrogen treatment of ovariectomized mice [13].
• In summary, ZEB1 is normally regulated by both estrogen and progesterone receptors, but in uterine cancers, it is likely no longer under control of steroid hormone receptors and becomes aberrantly expressed in epithelial-derived tumor cells, supporting a role for ZEB1 in epithelial to mesenchymal transitions associated with aggressive tumors [13].
• Conversely, doxorubicin was found to inhibit NIL2A complex formation 50% at less than 1 microM, but did not achieve this level of inhibition of EGR1/DNA complex formation even at 50 microM [14].
• Our results show that BZP/TFMPP and MDMA share the ability to evoke monoamine release, but dangerous drug-drug synergism may occur when piperazines are coadministered at high doses [15].

Regulatory relationships of ZEB1

• A working model is presented to account for the role of DNA-PK and AREB6-like proteins in regulating hXOR activity [16].

Other interactions of ZEB1

• However, the association between SNAIL and CDH1 was not found in patients with high expression of ZEB1 [1].
• Snail induction of epithelial to mesenchymal transition in tumor cells is accompanied by MUC1 repression and ZEB1 expression [11].
• Recent data provide evidence for interacting roles of ZEB1, p300, and a polymorphic 73 bp deletion in intron 1 of the human TP73 gene in this process [17].
• The mRNA expression levels of SNAIL and ZEB1, and of transcriptional regulators p300 and CtBP, were measured by RT-PCR in tumor and normal tissue from 101 colon carcinoma patients [2].
• Furthermore, when there were elevated p300 expression levels, the correlation between expression of ZEB1 and VDR was stronger (r = 0.38; p = 0.070) [2].

Analytical, diagnostic and therapeutic context of ZEB1

• Fluorescent in situ hybridization is employed to localize TCF8 to 10p11.2 [8].
• We further demonstrated interactions between the AREB6 repression domain and NC2alpha in yeast two-hybrid assay [9].
• PGE(2) exposure led to enhanced ZEB1 and Snail binding at the chromatin level as determined by chromatin immunoprecipitation assays [4].
• Western blot analysis demonstrates two forms of Zfhep with different mobilities [18].
• Pull-down and immunoprecipitation analyses demonstrated the binding of Ku86 to AREB6-like proteins [16].

References