ZONAB Promotes Proliferation and Represses Differentiation of Proximal Tubule Epithelial Cells

• Published in: Journal of the American Society of Nephrology 2010-03, Vol.21 (3), p.478-488
• Main Authors: LIMA, Wânia R, PARREIRA, Kleber S, TERZI, Fabiola, MATTER, Karl, BALDA, Maria S, PIERREUX, Christophe E, COURTOY, Pierre J, DEVUYST, Olivier, CAPLANUSI, Adrian, N'KULI, Francisca, MARIEN, Benoit, VAN DER SMISSEN, Patrick, ALVES, Pedro M. S, VERROUST, Pierre, CHRISTENSEN, Erik I
• Format: Article
• Language: English
• Subjects: Adenocarcinoma, Clear Cell - pathology; Adenocarcinoma, Clear Cell - physiopathology; Adult; Animals; Basic Research; Biological and medical sciences; CCAAT-Enhancer-Binding Proteins - genetics; CCAAT-Enhancer-Binding Proteins - metabolism; Cell Differentiation - physiology; Cell Division - physiology; Cell Line, Tumor; Cell Polarity - physiology; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Down-Regulation - physiology; Epithelial Cells - cytology; Epithelial Cells - physiology; Gene Expression Regulation, Developmental; Heat-Shock Proteins - genetics; Heat-Shock Proteins - metabolism; Humans; Kidney Neoplasms - pathology; Kidney Neoplasms - physiopathology; Kidney Tubules, Proximal - cytology; Kidney Tubules, Proximal - embryology; Kidney Tubules, Proximal - physiology; Low Density Lipoprotein Receptor-Related Protein-2 - genetics; Medical sciences; Mice; Mice, Inbred C57BL; Nephrology. Urinary tract diseases; Opossums; Promoter Regions, Genetic - physiology; Receptors, Cell Surface - genetics; RNA, Messenger - metabolism; Transcription Factors; Transfection
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2009070698

Epithelial polarization modulates gene expression. The transcription factor zonula occludens 1 (ZO-1)-associated nucleic acid binding protein (ZONAB) can shuttle between tight junctions and nuclei, promoting cell proliferation and expression of cyclin D1 and proliferating cell nuclear antigen (PCNA), but whether it also represses epithelial differentiation is unknown. Here, during mouse kidney ontogeny and polarization of proximal tubular cells (OK cells), ZONAB and PCNA levels decreased in parallel and inversely correlated with increasing apical differentiation, reflected by expression of megalin/cubilin, maturation of the brush border, and extension of the primary cilium. Conversely, ZONAB reexpression and loss of apical differentiation markers provided a signature for renal clear cell carcinoma. In confluent OK cells, ZONAB overexpression increased proliferation and PCNA while repressing megalin/cubilin expression and impairing differentiation of the brush border and primary cilium. Reporter and chromatin immunoprecipitation assays demonstrated that megalin and cubilin are ZONAB target genes. Sparsely plated OK cells formed small islands composed of distinct populations: Cells on the periphery, which lacked external tight junctions, strongly expressed nuclear ZONAB, proliferated, and failed to differentiate; central cells, surrounded by continuous junctions, lost nuclear ZONAB, stopped proliferating, and engaged in apical differentiation. Taken together, these data suggest that ZONAB is an important component of the mechanisms that sense epithelial density and participates in the complex transcriptional networks that regulate the switch between proliferation and differentiation.