Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan and activity are regulated by growth factor signaling networks. Growth factors activate phosphatidylinositol 3-kinase (PI3K), which enhances cell survival and antagonizes apoptosis through activation of Akt/PKB. This process is negatively regulated by the Pten phosphatase, which inhibits the activity of PI3K. In this study, we investigated the effects of Akt activation in bone in vivo by conditionally disrupting the Pten gene in osteoblasts by using Cre-mediated recombination. Mice deficient in Pten in osteoblasts were of normal size but demonstrated a dramatic and progressively increasing bone mineral density throughout life. In vitro osteoblasts lacking Pten differentiated more rapidly than controls and exhibited greatly reduced apoptosis in association with markedly increased levels of phosphorylated Akt and activation of signaling pathways downstream of activated Akt. These findings support a critical role for this tumor-suppressor gene in regulating osteoblast lifespan and likely explain the skeletal abnormalities in patients carrying germ-line mutations of PTEN.Akt ͉ bone acquisition ͉ osteoblast survival ͉ high bone mass T he development and maintenance of the mammalian skeleton are controlled by actions of morphogens and growth factors on bone cells. Bone formation is carried out by the osteoblast, a mesenchymal cell whose lifespan and activity are regulated by growth factor signaling networks (1, 2). Skeletal growth factors such as insulin-like growth factor-1 (IGF-1) affect osteoblast proliferation and lifespan by activating anti-apoptotic pathways, increasing cell proliferation, and influencing differentiation (3). A key control point in many anti-apoptotic pathways is the lipid kinase phosphatidylinositol (PI) 3-kinase (PI3K), which is activated in response to various extracellular signals (4, 5). On activation of growth factor receptor tyrosine kinases, a p85 regulatory subunit of PI3K is recruited to phosphorylated tyrosine residues. This action engages and activates a catalytic subunit (p110) and induces phosphorylation of the inositol ring of PI(4)P or PI(4,5)P 2 at the D position to generate the second messengers PI(3,4)P 2 and PI(3,4,5)P 3 (4, 5). A key downstream target of PI3K and PIP 3 is the serine-threonine Akt kinase family (also known as protein kinase B). PIP 3 generated in the plasma membrane recruits Akt and PI-dependent kinase 1 (PDK1) through an interaction between the PI and the Akt or PDK1 pleckstrin homology (PH) domains. Once recruited to the plasma membrane, Akt is phosphorylated and activated by PDK1.
This analysis examines supranational constitutionalism in the European Union. In particular, the study focuses on the role of the European Court of Justice in the creation of women's rights. I examine the interaction between the Court and member state governments in legal integration, and also the integral role that women's advocates -both individual activists and groups -have played in the development of EU social provisions. The findings suggest that this litigation dynamic can have the effect of fueling the integration process by creating new rights that may empower social actors and EU organizations, with the ultimate effect of diminishing member state government control over the scope and direction of EU law. This study focuses specifically on gender equality law, yet provides a general framework for examining the case law in subsequent legal domains, with the purpose of providing a more nuanced understanding of supranational governance and constitutionalism.
The European Union today stands on the brink of radical institutional and constitutional change. The most recent enlargement and proposed legal reforms reflect a commitment to democracy: stabilizing political life for citizens governed by new regimes, and constructing a European Union more accountable to civil society. Despite the perceived novelty of these reforms, this book explains (through quantitative data and qualitative case analyses) how the European Court of Justice has developed and sustained a vibrant tradition of democratic constitutionalism since the 1960s. The book documents the dramatic consequences of this institutional change for civil society and public policy reform throughout Europe. Cichowski offers detailed empirical and historical studies of gender equality and environmental protection law across fifteen countries and over thirty years, revealing important linkages between civil society, courts and the construction of governance. The findings bring into question dominant understandings of legal integration.
This article examines the connection between rights, courts, and the changing nature of democratic participation. The general comparative model developed is then applied to a time-series analysis of the European Court of Human Rights (ECHR). The article is the first to offer a systematic social science analysis of ECHR decisions with particular emphasis on changing democratic opportunities for individuals at both the domestic and supranational level. The findings reveal how rights and access to legal institutions shape the way courts serve as arenas for public participation-a consequence that brings into question dominant theories of international organization and comparative studies of judicial politics. C itizens around the world are demanding more participation in their democracy and a greater power over their governments. Courts are at the core of this transformation. Scholars have observed a growing change in democratic governance reflected by a general shift away from the traditional institutions of representative democracy and instead governance characterized both by the demand for and the attainment of greater citizen access, 50
Are international courts and advocacy group legal mobilization shaping human rights politics? This question poses a theoretical and empirical challenge to state dominated understandings of international litigation. This article theorizes the interaction between advocacy groups and the European Court of Human Rights and the role this participation plays in the enforcement and development of human rights. The analyses examine institutional factors shaping broad trends in mobilization complemented by two in depth studies examining a single mode of participation, amicus curiae and a single area of law, violence against women. The data identify the critical role standing rules, court review powers and group expertise play in transnational rights mobilization and development. The findings bring into question dominant understandings of international law and contribute to a more complex understanding of law in a global age where international courts and societal actors are shaping the direction of rights protection.
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