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A model for potential mechanisms by which miRNAs regulate cyst growth. miR-17 promotes proliferation of cyst epithelia and reduces ADPKD gene dosage. miR-21 inhibits apoptosis and thus, promotes survival of cyst epithelial cells. miR-200 reduces Pkd1 gene dosage and inhibits epithelial to mesenchymal transition (EMT). Loss of miR-200 may result in partial-EMT and increased Pkd1 dosage, which collectively may aggravate cyst growth.

Intramolecular triplex DNA. A) A schematic representation of an Hy-3 type intramolecular triplex is shown, formed within a mirror repeat sequence of (GAA)_n•(TTC)_n. B) AFM image of a 46 Pu•Py tract from a region of the human PKD1 gene in a triplex conformation within a plasmid DNA.

The roles of histone deacetylases (HDACs), Bromodomain proteins (BRDs) and DNA methyl transferases (DNMTs) in renal epithelial cells. In this schematic diagram, we depicted the roles of HDACs in regulating PKD1 gene expression and PKD associated signaling, including that i) HDAC5 is the target of fluid flow-induced calcium signal in renal epithelial cells; ii) HDAC6 and SIRT2 regulate cilia disassembly through deacetylation of α-tubulin during the normal cell cycle; iii) HDAC6 regulates epidermal growth factor receptor (EGFR) trafficking through deacetylation of α-tubulin; and iv) HDAC6 either alone or with EGF regulates β-catenin nuclear translocation. We also indicate the potential roles of DNMTs in regulating the transcription of PKD1 gene, other PKD genes and PKD-associated genes. The roles of BRDs in regulating the transcription of c-Myc and the components of Hedgehog signaling are also included. The involvement of calcium signaling in these processes is possible but is uncertain.

Signaling and regulation of TRPP2 channels. This illustration depicts the different models for the localization-dependent functions of TRPP2. TRPP2 mediates Ca²⁺ influx at the plasma membrane (PM) and the ciliary membrane (cilium), where it functions in a heteromultimeric protein complex with PKD1 (1, 3) and possibly with other members of the TRP channel superfamily (TRPC1, TRPV4) (2). PKD1 is known to activate multiple signaling pathways via G proteins, a process that can be regulated by physical interaction with TRPP2. Calcium influx induced by shear flow in renal epithelial cells is triggered by bending the primary cilium and seemingly requires the PKD1–TRPP2 complex in the luminal cilium (3). Mechanical stress activates PKD1–TRPP2 complexes to allow Ca²⁺ influx either in the shaft or in the base of the primary cilium. TRPP2 acts as a Ca²⁺-release channel in the endoplasmic reticulum (ER), where it might interact with and regulate IP₃Rs (4). Serine-phosphorylated TRPP2 sequesters Id2 in the cytoplasm and normally prevents Id2 from entering the nucleus and binding to E-proteins (5). PKD1 can undergo a proteolytic cleavage that releases its C-terminal tail, which translocates to the nucleus and activates the transcription factor AP-1 (6). Note that we hypothetized that PKD1 targeted to the primary cilium is also cleaved at its GPS site. See text for more details. Abbreviations: PKC, protein kinase C; PKA, cAMP-dependent protein kinase; NFAT, nuclear factor of activated T-cells; PI3K, phosphatidylinositol 3-kinase; MEK, mitogen-activated protein kinase/ERK kinase; ERK, extracellular signal-regulated kinase.