Identification of a Polycystin-1 Cleavage Product, P100, That Regulates Store Operated Ca2+ Entry through Interactions with STIM1

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a genetic disorder resulting in large kidney cysts and eventual kidney failure. Mutations in either the PKD1 or PKD2/TRPP2 genes and their respective protein products, polycystin-1 (PC1) and polycystin-2 (PC2) result in ADPKD. PC2 is known to function as a non-selective cation channel, but PC1's function and the function of PC1 cleavage products are not well understood. Here we identify an endogenous PC1 cleavage product, P100, a 100 kDa fragment found in both wild type and epitope tagged PKD1 knock-in mice. Expression of full length human PC1 (FL PC1) and the resulting P100 and C-Terminal Fragment (CTF) cleavage products in both MDCK and CHO cells significantly reduces the store operated Ca2+ entry (SOCE) resulting from thapsigargin induced store depletion. Exploration into the roles of P100 and CTF in SOCE inhibition reveal that P100, when expressed in Xenopus laevis oocytes, directly inhibits the SOCE currents but CTF does not, nor does P100 when containing the disease causing R4227X mutation. Interestingly, we also found that in PC1 expressing MDCK cells, translocation of the ER Ca2+ sensor protein STIM1 to the cell periphery was significantly altered. In addition, P100 Co-immunoprecipitates with STIM1 but CTF does not. The expression of P100 in CHO cells recapitulates the STIM1 translocation inhibition seen with FL PC1. These data describe a novel polycystin-1 cleavage product, P100, which functions to reduce SOCE via direct inhibition of STIM1 translocation; a function with consequences for ADPKD

The ethics of evaluating obesity intervention studies on children

The methodology of the IDEFICS (Identification and prevention of dietary- and lifestyle-induced health effects in children and infants) study raises a number of important ethical questions. Many of these are already well recognised in ethical guidelines that uphold principles of individual and parental consent, confidentiality and scientific review. There are, however, wider issues that require ethical reflection. In this paper, we focus on a set of problems surrounding the evaluation of complex social interventions, and argue that comprehensive and objective evaluation is a much more ethically charged aim than it may first appear. In particular, we contend that standard scientific measuresFof body size and biomarkersFconvey only part of the story. This is partly because, when we intervene in communities, we are also concerned with complex social effects. These effects are made even more complex by contemporary social anxieties about fat and physical appearance, as well as about the safety and security of children. Such anxieties increase the risk of undesirable side effects that are themselves difficult to gauge. In the face of these and other complexities, we argue that the evaluation of interventions should involve a strong ethical dimension. First, it must includeFas does the IDEFICS studyFconsideration of the opinions of the people affected, who are subjected to interventions in ways that necessarily go beyond individual consent. Second, we suggest that interventions might also be assessed by how much they empower peopleFand especially those persons, such as children, who are otherwise often disempowered