The Cilium: Cellular Antenna and Central Processing Unit

Cilia mediate an astonishing diversity of processes. Recent advances provide unexpected insights into the regulatory mechanisms of cilium formation, and reveal diverse regulatory inputs that are related to the cell cycle, cytoskeleton, proteostasis, and cilia-mediated signaling itself. Ciliogenesis and cilia maintenance are regulated by reciprocal antagonistic or synergistic influences, often acting in parallel to each other. By receiving parallel inputs, cilia appear to integrate multiple signals into specific outputs and may have functions similar to logic gates of digital systems. Some combinations of input signals appear to impose higher hierarchical control related to the cell cycle. An integrated view of these regulatory inputs will be necessary to understand ciliogenesis and its wider relevance to human biology

The Centrosomal Kinase Plk1 Localizes to the Transition Zone of Primary Cilia and Induces Phosphorylation of Nephrocystin-1

Polo-like kinase (Plk1) plays a central role in regulating the cell cycle. Plk1-mediated phosphorylation is essential for centrosome maturation, and for numerous mitotic events. Although Plk1 localizes to multiple subcellular sites, a major site of action is the centrosomes, which supports mitotic functions in control of bipolar spindle formation. In G0 or G1 untransformed cells, the centriolar core of the centrosome differentiates into the basal body of the primary cilium. Primary cilia are antenna-like sensory organelles dynamically regulated during the cell cycle. Whether Plk1 has a role in ciliary biology has never been studied. Nephrocystin-1 (NPHP1) is a ciliary protein; loss of NPHP1 in humans causes nephronophthisis (NPH), an autosomal-recessive cystic kidney disease. We here demonstrate that Plk1 colocalizes with nephrocystin-1 to the transition zone of primary cilia in epithelial cells. Plk1 co-immunoprecipitates with NPHP1, suggesting it is part of the nephrocystin protein complex. We identified a candidate Plk1 phosphorylation motif (D/E-X-S/T-φ-X-D/E) in nephrocystin-1, and demonstrated in vitro that Plk1 phosphorylates the nephrocystin N-terminus, which includes the specific PLK1 phosphorylation motif. Further, induced disassembly of primary cilia rapidly evoked Plk1 kinase activity, while small molecule inhibition of Plk1 activity or RNAi-mediated downregulation of Plk1 limited the first and second phase of ciliary disassembly. These data identify Plk1 as a novel transition zone signaling protein, suggest a function of Plk1 in cilia dynamics, and link Plk1 to the pathogenesis of NPH and potentially other cystic kidney diseases

Estrogen receptor alpha (ER alpha) indirectly induces transcription of human renal organic anion transporter 1 (OAT1)

Organic anion transporter 1 (OAT1) is a polyspecific transport protein located in the basolateral membrane of renal proximal tubule cells. OAT1 plays a pivotal role in drug clearance. Adverse drug reactions (ADR) are observed more frequently in women than in men, especially ADR are higher in women for drugs which are known interactors of OAT1. Sex-dependent expression of Oat1 has been observed in rodents with a tendency to male-dominant expression. This study aims at elucidating the transcriptional regulation of human OAT1 and tests the effect of estrogen receptor alpha (ER alpha). Promoter activation of OAT1 was assessed by luciferase assays carried out by Opossum kidney (OK) cells, transiently transfected with promoter constructs of human OAT1 and expression vectors for ER alpha and exposed to 100 nmol/L 17 beta-estradiol. Furthermore, a transcription factor array and proteomic analysis was performed to identify estrogen-induced transcription factors. Human OAT1 was significantly activated by ligand activated ER alpha. However, activation occurred without a direct interaction of ER alpha with the OAT1 promoter. Our data rather show an activation of the transcription factors CCAAT-box-binding transcription factor (CBF) and heterogeneous nuclear ribonucleoprotein K (HNRNPK) by ER alpha, which in turn bind and initiate OAT1 promoter activity. Herewith, we provide novel evidence of estrogen-dependent, transcriptional regulation of polyspecific drug transporters including the estrogen-induced transcription factors CBF and HNRNPK

GHetting to know ADPKD proliferative signaling, STAT

Due to their common pathogenesis and parallel proliferative signaling pathways, the cystic diseases have been recently studied in the context of cancer biology. The present study continues this paradigm by identifying signal transducer and activator of transcription (STAT5) and growth hormone (GH) as potentially modifiable pathways in polycystic kidney disease. GH, which is a potent activator of STAT5, has the additional possibility of being a biomarker, as well as providing a potential mechanism of action of somatostatin analogs in clinical trials