Anticancer drug therapy activates both molecular cell death and autophagy pathways. Here we show that even sublethal concentrations of DNA-damaging drugs, such as etoposide and cisplatin, induce the expression of autophagy-related protein 5 (ATG5), which is both necessary and sufficient for the subsequent induction of mitotic catastrophe. We demonstrate that ATG5 translocates to the nucleus, where it physically interacts with survivin in response to DNA-damaging agents both in vitro and in carcinoma tissues obtained from patients who had undergone radiotherapy and/or chemotherapy. As a consequence, elements of the chromosomal passenger complex are displaced during mitosis, resulting in chromosome misalignment and segregation defects. Pharmacological inhibition of autophagy does not prevent ATG5-dependent mitotic catastrophe, but shifts the balance to an early caspase-dependent cell death. Our data suggest a dual role for ATG5 in response to drug-induced DNA damage, where it acts in two signalling pathways in two distinct cellular compartments, the cytosol and the nucleus.

WNT ligands induce Ca2+ signaling on target cells. PKD1 (Polycystin 1) is considered an orphan, atypical G protein coupled receptor complexed with TRPP2 (Polycystin 2 or PKD2), a Ca2+-permeable ion channel. Inactivating mutations in their genes cause autosomal dominant polycystic kidney disease (ADPKD), one of the most common genetic diseases. Here, we show that WNTs bind to the extracellular domain of PKD1 and induce whole cell currents and Ca2+ influx dependent on TRPP2. Pathogenic PKD1 or PKD2 mutations that abrogate complex formation, compromise cell surface expression of PKD1, or reduce TRPP2 channel activity suppress activation by WNTs. Pkd2−/− fibroblasts lack WNT-induced Ca2+ currents and are unable to polarize during directed cell migration. In Xenopus embryos, PKD1, Dishevelled 2 (DVL2), and WNT9A act within the same pathway to preserve normal tubulogenesis. These data define PKD1 as a WNT (co)receptor and implicate defective WNT/Ca2+ signaling as one of the causes of ADPKD.

Primary cilia start forming within the G1 phase of the cell cycle and continue to grow as cells exit the cell cycle (G0). They start resorbing when cells re-enter the cell cycle (S phase) and are practically invisible in mitosis. The mechanisms by which cilium biogenesis and disassembly are coupled to the cell cycle are complex and not well understood. We previously identified the centrosomal phosphoprotein NDE1 as a negative regulator of ciliary length and showed that its levels inversely correlate with ciliogenesis. Here, we identify the tumor suppressor FBW7 (also known as FBXW7, CDC4, AGO, or SEL-10) as the E3 ligase that mediates the destruction of NDE1 upon entry into G1. CDK5, a kinase active in G1/G0, primes NDE1 for FBW7-mediated recognition. Cells depleted of FBW7 or CDK5 show enhanced levels of NDE1 and a reduction in ciliary length, which is corrected in cells depleted of both FBW7 or CDK5 and NDE1. These data show that cell cycle-dependent mechanisms can control ciliary length through a CDK5-FBW7-NDE1 pathway.

Cilia and flagella are evolutionarily conserved, membrane-bound, microtubule-based organelles on the surface of most eukaryotic cells. They play important roles in coordinating a variety of signaling pathways during growth, development, cell mobility, and tissue homeostasis. Defects in ciliary structure or function are associated with multiple human disorders called ciliopathies. These diseases affect diverse tissues, including, but not limited to the eyes, kidneys, brain, and lungs. Many processes must be coordinated simultaneously in order to initiate ciliogenesis. These include cell cycle, vesicular trafficking, and axonemal extension. Centrioles play a central role in both cell cycle progression and ciliogenesis, making the transition between basal bodies and mitotic spindle organizers integral to both processes. The maturation of centrioles involves a functional shift from cell division toward cilium nucleation which takes place concurrently with its migration and fusion to the plasma membrane. Several proteinaceous structures of the distal appendages in mother centrioles are required for this docking process. Ciliary assembly and maintenance requires a precise balance between two indispensable processes; so called assembly and disassembly. The interplay between them determines the length of the resulting cilia. These processes require a highly conserved transport system to provide the necessary substances at the tips of the cilia and to recycle ciliary turnover products to the base using a based microtubule intraflagellar transport (IFT) system. In this review; we discuss the stages of ciliogenesis as well as mechanisms controlling the lengths of assembled cilia.

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