Zeb1 links epithelial-mesenchymal transition and cellular senescence.
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.
Liu
Yongqing
Y
James Graham Brown Cancer Center, Department of Ophthalmology and Visual Sciences, University of Louisville Health Sciences Center, Louisville, KY 40202, USA.
El-Naggar
Shahenda
S
Darling
Douglas S
DS
Higashi
Yujiro
Y
Dean
Douglas C
DC
D000818:Animals; D001921:Brain / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002356:Cartilage / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D049109:Cell Proliferation / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D004848:Epithelium / Q000187:drug effects / Q000196:embryology*; D005123:Eye / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D018628:Gene Dosage; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000196:embryology*; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics; D010159:Palate / Q000166:cytology / Q000187:drug effects / Q000196:embryology; D012097:Repressor Proteins / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D014746:Vimentin / Q000235:genetics / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; C493968:Cdkn2b protein, mouse; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D051741:Kruppel-Like Transcription Factors; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D014746:Vimentin; C519422:ZEB1 protein, mouse; D000071799:Zinc Finger E-box-Binding Homeobox 1