Zeb1 links epithelial-mesenchymal transition and cellular senescence

Abstract

Overexpression of zinc finger E-box binding homeobox transcription factor 1 (Zeb1) in cancer leads to epithelial-to-mesenchymal transition (EMT) and increased metastasis. As opposed to overexpression, we show that mutation of Zeb1 in mice causes a mesenchymal-epithelial transition in gene expression characterized by ectopic expression of epithelial genes such as E-cadherin and loss of expression of mesenchymal genes such as vimentin. In contrast to rapid proliferation in cancer cells where Zeb1 is overexpressed, this mesenchymal-epithelial transition in mutant mice is associated with diminished proliferation of progenitor cells at sites of developmental defects, including the forming palate, skeleton and CNS. Zeb1 dosage-dependent deregulation of epithelial and mesenchymal genes extends to mouse embryonic fibroblasts (MEFs), and mutant MEFs also display diminished replicative capacity in culture, leading to premature senescence. Replicative senescence in MEFs is classically triggered by products of the Ink4a (Cdkn2a) gene. However, this Ink4a pathway is not activated during senescence of Zeb1 mutant MEFs. Instead, there is ectopic expression of two other cell cycle inhibitory cyclin-dependent kinase inhibitors, p15Ink4b (Cdkn2b) and p21Cdkn1a (Cdkn1a). We demonstrate that this ectopic expression of p15Ink4b extends in vivo to sites of diminished progenitor cell proliferation and developmental defects in Zeb1-null mice.

The EMT activator ZEB1 promotes tumor growth and determines differential response to chemotherapy in mantle cell lymphoma

“…1,40,43,44 ZEB1 is known to be repressed by Rb1 and in turn to repress several cyclin-dependent kinase inhibitors (for example, p15 INK4b , p19 ARF , and p21 CIP/WAF1 ). [45][46][47] In several hematological malignancies, including MCLs, Wnt signaling enhances cell viability, whereas its inhibition reduces it. 5,15,17,18,20 We therefore questioned whether ZEB1 determines enhanced cell viability in MCL cells.…”

The microRNA network and tumor metastasis

“…Feedback loops feature in a number of genetic pathways involving miRNAs, in which they seem to enhance the functionality and robustness of gene networks. Otherwise, because ZEB1 is crucial for TGF-b-mediated EMT in various steps in organogenesis (Liu et al, 2008), the reciprocal negative feedback loop between ZEB1/ZEB2 Figure 1 Pathways of reciprocal negative feedback mediated by the miR-200 family in regulating epithelial-mesenchymal transition (EMT). In the nucleus, the pre-miR-200 family (include pre-miR-200a, pre-miR-200b, pre-miR-200c, pre-miR-429 and pre-miR-141) are transcribed and processed from miRNA genes in chromatin 1 and 12.…”

Heterozygous deletions at the ZEB1 locus verify haploinsufficiency as the mechanism of disease for posterior polymorphous corneal dystrophy type 3

“…31 Conversely, enhanced expression of epithelial-specific genes in this pathway, including E-cadherin (CDH1) and COL4A3, has been demonstrated in embryonic null and adult haploinsufficient ZEB1 mice. 20,30 Importantly, the mice display abnormal corneal endothelial and keratocyte proliferation, as well as abnormal posterior corneal morphology, mimicking the PPCD3 phenotype. 30 Interestingly, the corneal endothelium from PPCD3 patients exhibits increased expression of markers for an epithelial cell phenotype, such as keratins 7 and 19.…”

“…9,14,16,19 ZEB1 encodes a zinc finger transcription factor (zinc finger E-box binding homeobox 1) that has a role in many cellular processes, including epithelial-mesenchymal transition (EMT) that involves the transformation of adhesive, non-mobile, epithelial cells into cells with a mesenchymal phenotype that have the ability to migrate. 20,21 ZEB1 induces EMT by suppressing the expression of epithelial-specific factors such as E-cadherin. 22 EMT is crucial in early embryogenesis for delamination of the neural crest from the neural tube and for defining the ectodermal-mesodermal boundary.…”

“…23 ZEB1 is also thought to have a role in neural crest cell migration and the subsequent development of derivative structures, such as the corneal endothelium. 20,24 PPCD often presents in small nuclear families or as an isolated case such that linkage to a specific genomic region is not conclusive, or is confounded by incomplete penetrance in some cases, so a substantial proportion of patients currently lack a molecular diagnosis. [9][10][11][12][14][15][16][17] In this study we demonstrate that, in some of these cases, PPCD can be attributed to heterozygous deletions at the ZEB1 locus, providing insights into the molecular diagnosis of previously unexplained PPCD cases and verifying haploinsufficiency as the mechanism of disease for PPCD3.…”