Tacrolimus ameliorates podocyte injury by restoring FK506 binding protein 12 (FKBP12) at actin cytoskeleton

The highly conserved 14-3-3 protein family has risen to a position of importance in cell biology owing to its involvement in vital cellular processes, such as metabolism, protein trafficking, signal transduction, apoptosis and cell-cycle regulation. The 14-3-3 proteins are phospho-serine/phospho-threonine binding proteins that interact with a diverse array of binding partners. Because many 14-3-3 interactions are phosphorylation-dependent, 14-3-3 has been tightly integrated into the core phospho-regulatory pathways that are crucial for normal growth and development and that often become dysregulated in human disease states such as cancer. This review examines the recent advances that further elucidate the role of 14-3-3 proteins as integrators of diverse signaling cues that influence cell fate decisions and tumorigenesis.

This chapter includes a historic overview of 14-3-3 proteins with an emphasis on the differences between potentially cancer-relevant isoforms on the genomic, protein and functional level. The focus will therefore be on mammalian 14-3-3s although many important developments in the field have involved Drosophila 14-3-3 proteins for example and the cross-fertilisation from parallel studies on plant 14-3-3 should not be underestimated. In the major part of this review I will attempt to focus on some novel data and aspects of 14-3-3 structure and function, in particular regulation of 14-3-3 isoforms by oncogene-related protein kinase phosphorylation and aspects of 14-3-3 research with which newcomers to the field may be less familiar.

Recent molecular insights have established the podocyte as a key component of the glomerular filtration barrier, and hence an important common pathway in proteinuric diseases. A conditionally immortalized human podocyte cell line has been developed by transfection with the temperature-sensitive SV40-T gene. These cells proliferate at the "permissive" temperature (33 degrees C). After transfer to the "nonpermissive" temperature (37 degrees C), they entered growth arrest and expressed markers of differentiated in vivo podocytes, including the novel podocyte proteins, nephrin, podocin, CD2AP, and synaptopodin, and known molecules of the slit diaphragm ZO-1, alpha-, beta-, and gamma-catenin and P-cadherin. The differentiation was accompanied by a growth arrest and the upregulation of cyclin-dependent kinase inhibitors, p27 and p57, as well as cyclin D(1), whereas cyclin A was downregulated. These data are consistent with cell cycle protein expression during podocyte maturation in vivo. In conclusion, the development of this cell line provides a new tool in the study of podocyte biology, which will enable accurate assessment of the behavior of these complex cells in health and disease.