Novel role for polycystin-1 in modulating cell proliferation through calcium oscillations in kidney cells

Objectives: Polycystin-1 (PC1), a signalling receptor regulating Ca2+-permeable cation channels, is mutated in autosomal dominant polycystic kidney disease, which is typically characterized by increased cell proliferation. However, the precise mechanisms by which PC1 functions on Ca2+ homeostasis, signalling and cell proliferation remain unclear. Here, we investigated the possible role of PC1 as a modulator of non-capacitative Ca2+ entry (NCCE) and Ca2+ oscillations, with downstream effects on cell proliferation. Results and discussion: By employing RNA interference, we show that depletion of endogenous PC1 in HEK293 cells leads to an increase in serum-induced Ca2+ oscillations, triggering nuclear factor of activated T cell activation and leading to cell cycle progression. Consistently, Ca2+ oscillations and cell proliferation are increased in PC1-mutated kidney cystic cell lines, but both abnormal features are reduced in cells that exogenously express PC1. Notably, blockers of the NCCE pathway, but not of the CCE, blunt abnormal oscillation and cell proliferation. Our study therefore provides the first demonstration that PC1 modulates Ca2+ oscillations and a molecular mechanism to explain the association between abnormal Ca2+ homeostasis and cell proliferation in autosomal dominant polycystic kidney disease

Polycystin-1 promotes PKC alpha-mediated NF-kappa B activation in kidney cells

Polycystin-1 (PC1), the PKD1 gene product, is a membrane receptor which regulates many cell functions, including cell proliferation and apoptosis, both typically increased in cyst lining cells in autosomal dominant polycystic kidney disease. Here we show that PC1 upregulates the NF-kappaB signalling pathway in kidney cells to prevent cell death. Human embryonic kidney cell lines (HEK293(CTT)), stably expressing a PC1 cytoplasmic terminal tail (CTT), presented increased NF-kappaB nuclear levels and NF-kappaB-mediated luciferase promoter activity. This, consistently, was reduced in HEK293 cells in which the endogenous PC1 was depleted by RNA interference. CTT-dependent NF-kappaB promoter activation was mediated by PKCalpha because it was blocked by its specific inhibitor Ro-320432. Furthermore, it was observed that apoptosis, which was increased in PC1-depleted cells, was reduced in HEK293(CTT) cells and in porcine kidney LtTA cells expressing a doxycycline-regulated CTT. Staurosporine, a PKC inhibitor, and parthenolide, a NF-kappaB inhibitor, significantly reduced the CTT-dependent antiapoptotic effect. These data reveal, therefore, a novel pathway by which polycystin-1 activates a PKCalpha-mediated NF-kappaB signalling and cell survival

Polycystin-1 promotes PKC alpha-mediated NF-kappa B activation in kidney cells

Polycystin-1 (PC1), the PKD1 gene product, is a membrane receptor which regulates many cell functions, including cell proliferation and apoptosis, both typically increased in cyst lining cells in autosomal dominant polycystic kidney disease. Here we show that PC1 upregulates the NF-kappaB signalling pathway in kidney cells to prevent cell death. Human embryonic kidney cell lines (HEK293(CTT)), stably expressing a PC1 cytoplasmic terminal tail (CTT), presented increased NF-kappaB nuclear levels and NF-kappaB-mediated luciferase promoter activity. This, consistently, was reduced in HEK293 cells in which the endogenous PC1 was depleted by RNA interference. CTT-dependent NF-kappaB promoter activation was mediated by PKCalpha because it was blocked by its specific inhibitor Ro-320432. Furthermore, it was observed that apoptosis, which was increased in PC1-depleted cells, was reduced in HEK293(CTT) cells and in porcine kidney LtTA cells expressing a doxycycline-regulated CTT. Staurosporine, a PKC inhibitor, and parthenolide, a NF-kappaB inhibitor, significantly reduced the CTT-dependent antiapoptotic effect. These data reveal, therefore, a novel pathway by which polycystin-1 activates a PKCalpha-mediated NF-kappaB signalling and cell survival

The Semantics of Entrepreneurial Learning in New Technology-Based Firms

New Technology-Based Firms (NTBFs) learn their business in the early-stages of their life-cycle. As a central element of the entrepreneurial learning process, the business model describes the value-creation functions that are conceptualized in different stages of the NTBF’s life-cycle. Transaction relations connect the model with the business reality and ideally mature in strength over time to a functioning value-network. This chapter describes the development of a research design that determines, extracts, and evaluates semantics constructs of this entrepreneurial learning out of a convenient sample and three cohorts of business plans submitted to a business plan award between 2008 and 2010. The analysis shows empirical evidence for the survival and growth of those NTBFs that exhibit a balanced status of entrepreneurial learning in the maturity of the value-network that can be characterized as early startup-stage. The empirical findings of the network theory based business plan analysis will allow for a better explanation of the performance in the entrepreneurial process that is discussed for NTBFs based on theory of organizational learning

Seven Contexts for Service System Design

Many of the most complex service systems being built and imagined today combine person-to-person encounters, technology-enhanced encounters, self-service, computational services, multi-channel, multidevice, and location-based and context-aware services. This paper examines the characteristic concerns and methods for these seven different design contexts to propose a unifying view that spans them, especially when the service-system is “information-intensive. ” A focus on the information required to perform the service, how the responsibility to provide this information is divided between the service provider and service consumer, and the patterns that govern information exchange yields a more abstract description of service encounters and outcomes. This makes it easier to see the systematic relationships among the contexts that can be exploited as design parameters or patterns, such as the substitutability of stored or contextual information for person-to-person interactions. A case study for the design of a “smart multichannel bookstore ” illustrates the use of the different design contexts as building blocks for service systems. 1