Zeb1 links epithelial-mesenchymal transition and cellular senescence

被引:241
作者
Liu, Yongqing [1 ]
El-Naggar, Shahenda [1 ]
Darling, Douglas S. [2 ,3 ,4 ]
Higashi, Yujiro [5 ]
Dean, Douglas C. [1 ]
机构
[1] Univ Louisville, Hlth Sci Ctr, James Graham Brown Canc Ctr, Dept Ophthalmol & Visual Sci, Louisville, KY 40202 USA
[2] Univ Louisville, Sch Dent, Dept Peiodont, Ctr Oral Hlth & Syst Dis, Louisville, KY 40292 USA
[3] Univ Louisville, Sch Dent, Dept Endodont, Ctr Oral Hlth & Syst Dis, Louisville, KY 40292 USA
[4] Univ Louisville, Sch Dent, Dept Dent Hyg, Ctr Oral Hlth & Syst Dis, Louisville, KY 40292 USA
[5] Osaka Univ, Grad Sch Frontier Biosci, Osaka, Japan
来源
DEVELOPMENT | 2008年 / 135卷 / 03期
关键词
Zeb1; epithelial-mesenchymal transition; senescence; transcription;
D O I
10.1242/dev.007047
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 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.
引用
收藏
页码:579 / 588
页数:10
相关论文
共 48 条
[1]  
Chamberlain EM, 1999, MOL CELL BIOL, V19, P3600
[2]   The transcriptional control of trunk neural crest induction, survival, and delamination [J].
Cheung, M ;
Chaboissier, MC ;
Mynett, A ;
Hirst, E ;
Schedl, A ;
Briscoe, J .
DEVELOPMENTAL CELL, 2005, 8 (02) :179-192
[3]   CtBP, an unconventional transcriptional corepressor in development and oncogenesis [J].
Chinnadurai, G .
MOLECULAR CELL, 2002, 9 (02) :213-224
[4]   Epigenetic targets in hematopoietic malignancies [J].
Claus, R ;
Lübbert, M .
ONCOGENE, 2003, 22 (42) :6489-6496
[5]   Human neuroblasts migrate to the olfactory bulb via a lateral ventricular extension [J].
Curtis, Maurice A. ;
Kam, Monica ;
Nannmark, Ulf ;
Anderson, Michelle F. ;
Axell, Mathilda Zetterstrom ;
Wikkelso, Carsten ;
Holtas, Stig ;
van Roon-Mom, Willeke M. C. ;
Bjork-Eriksson, Thomas ;
Nordborg, Claes ;
Frisen, Jonas ;
Dragunow, Michael ;
Faull, Richard L. M. ;
Eriksson, Peter S. .
SCIENCE, 2007, 315 (5816) :1243-1249
[6]   Expression of Zfhep/δEF1 protein in palate, neural progenitors, and differentiated neurons [J].
Darling, DS ;
Stearman, RP ;
Qi, YC ;
Qiu, MS ;
Feller, JP .
GENE EXPRESSION PATTERNS, 2003, 3 (06) :709-717
[7]   The zinc finger/homeodomain protein δEF1 mediates estrogen-specific induction of the ovalbumin gene [J].
Dillner, NB ;
Sanders, MM .
MOLECULAR AND CELLULAR ENDOCRINOLOGY, 2002, 192 (1-2) :85-91
[8]   DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells [J].
Eger, A ;
Aigner, K ;
Sonderegger, S ;
Dampier, B ;
Oehler, S ;
Schreiber, M ;
Berx, G ;
Cano, A ;
Beug, H ;
Foisner, R .
ONCOGENE, 2005, 24 (14) :2375-2385
[9]   DISPLACEMENT OF AN E-BOX-BINDING REPRESSOR BY BASIC HELIX-LOOP-HELIX PROTEINS - IMPLICATIONS FOR B-CELL SPECIFICITY OF THE IMMUNOGLOBULIN HEAVY-CHAIN ENHANCER [J].
GENETTA, T ;
RUEZINSKY, D ;
KADESCH, T .
MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (09) :6153-6163
[10]   Regulation of the INK4b-ARF-INK4a tumour suppressor locus:: all for one or one for all [J].
Gil, Jesus ;
Peters, Gordon .
NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2006, 7 (09) :667-677