ZONAB Promotes Proliferation and Represses Differentiation of Proximal Tubule Epithelial Cells

Abstract

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.

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

“…12,13 In addition to defective apical transport, abnormal proliferation is often observed in diseased PT cells. 13,24,33 Increased proliferation was consistently observed in kCH kidneys and mPTCs exposed to RFS-kLCs as indicated by the PCNA and cyclin-D1 markers and bromodeoxyuridine incorporation. Our data suggest the involvement of the Y-box transcription factor ZONAB, which is active during nephrogenesis and PT maturation.…”

Membrane-Initiated Estradiol Signaling of Epithelial-Mesenchymal Transition-Associated Mechanisms Through Regulation of Tight Junctions in Human Breast Cancer Cells

“…It has been reported that ZONAB and ZO-1 are part of a pathway by which TJs can regulate epithelial cell proliferation [33]. ZONAB is a Y-box transcription factor that binds to the ZO-1 SH3 domain and modulates the expression of genes encoding proteins involved in differentiation and cell proliferation in normal epithelial [34] and uveal melanoma cells [35]. Both proteins, after specific stimulus, localize in the nucleus and bind to specific promoters containing an inverted CCAAT box (Y-box).…”

Time Course of Pathogenic and Adaptation Mechanisms in Cystinotic Mouse Kidneys

“…Dedifferentiation before atrophy implies reversal of the apical differentiation program and might account for asynchrony between individual apical components as reported in cultured PTCs. 18 Long considered as degradative organelles, lysosomes emerge as signaling compartments that are able to impact on gene expression. 37 The signaling and transcriptional linkages between lysosomal expansion before crystals and repressed apical differentiation before atrophy deserve additional studies.…”

“…17 However, as shown in polarized PTCs cultures, expression of apical endocytic receptors strongly depends on differentiation state. 18 To address these issues, we exploited congenic Ctns 2/2 C57BL/6 mice, 5 which allowed us to study early kidney events that are inaccessible in patients. This established model shows (1) high cystine levels, , and RBP in one WT and two Ctns 2/2 mice (#1 and #2) in serial collections at the indicated ages (loads normalized to 2 mg creatinine).…”