Regulation of PCNA and cyclin D1 expression and epithelial morphogenesis by the ZO-1-regulated transcription factor ZONAB/DbpA

被引:184
作者
Sourisseau, T
Georgiadis, A
Tsapara, A
Ali, RR
Pestell, R
Matter, K
Balda, MS
机构
[1] UCL, Div Cell Biol, Inst Ophthalmol, London EC1V 9EL, England
[2] UCL, Div Mol Therapy, Inst Ophthalmol, London EC1V 9EL, England
[3] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
基金
英国惠康基金; 英国医学研究理事会; 英国生物技术与生命科学研究理事会;
关键词
D O I
10.1128/MCB.26.6.2387-2398.2006
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The tight junction protein ZO-1 inhibits G(1)/S-phase transition by cytoplasmic sequestration of a complex formed by CDK4 and the transcription factor ZONAB. Canine ZONAB is the homologue of human DbpA, an E2F target gene that is overexpressed in different carcinomas. Since the ZONAB target genes that are involved in G(1)/S-phase transition are unknown, we employed the mammary epithelial cell line MCF-10A and cDNA arrays to screen for such genes. We identified genes encoding cell cycle and replication proteins whose expression was altered due to increased ZONAB expression. For proliferative cell nuclear antigen and cyclin D1 genes, we show that increased mRNA levels resulted in increased protein levels and we identified ZONAB-responsive elements in their promoters by using different approaches, including chromatin immunoprecipitation assays. RNA interference and overexpression of ZONAB affected the proliferation of both MCF-10A and MDCK cells as well as the differentiation of MDCK cells into polarized cysts in three-dimensional cultures. these results indicate that ZONAB regulates the transcription of genes that are important for G(1)/S-phase progression and links tight junctions to the transcriptional control of key cell cycle regulators and epithelial cell differentiation.
引用
收藏
页码:2387 / 2398
页数:12
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