MicroRNAs are a class of small RNAs that are increasingly being recognized as important regulators of gene expression. Although hundreds of microRNAs are present in the mammalian genome, genetic studies addressing their physiological roles are at an early stage. We have shown that mice deficient for bic/microRNA-155 are immunodeficient and display increased lung airway remodeling. We demonstrate a requirement of bic/microRNA-155 for the function of B and T lymphocytes and dendritic cells. Transcriptome analysis of bic/microRNA-155-deficient CD4+ T cells identified a wide spectrum of microRNA-155-regulated genes, including cytokines, chemokines, and transcription factors. Our work suggests that bic/microRNA-155 plays a key role in the homeostasis and function of the immune system.

Class IA phosphoinositide 3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that generate second messenger signals downstream of tyrosine kinases, thereby controlling cell metabolism, growth, proliferation, differentiation, motility, and survival. Mammals express three class IA catalytic subunits: p110α, p110β, and p110δ. It is unclear to what extent these p110 isoforms have overlapping or distinct biological roles. Mice expressing a catalytically inactive form of p110δ (p110δ D910A ) were generated by gene targeting. Antigen receptor signaling in B and T cells was impaired and immune responses in vivo were attenuated in p110δ mutant mice. They also developed inflammatory bowel disease. These results reveal a selective role for p110δ in immunity.

Caloric restriction (CR) protects against aging and disease but the mechanisms by which this affects mammalian lifespan are unclear. We show in mice that deletion of the nutrient-responsive mTOR (mammalian target of rapamycin) signaling pathway component ribosomal S6 protein kinase 1 (S6K1) led to increased lifespan and resistance to age-related pathologies such as bone, immune and motor dysfunction and loss of insulin sensitivity. Deletion of S6K1 induced gene expression patterns similar to those seen in CR or with pharmacological activation of adenosine monophosphate (AMP)-activated protein kinase (AMPK), a conserved regulator of the metabolic response to CR. Our results demonstrate that S6K1 influences healthy mammalian lifespan, and suggest therapeutic manipulation of S6K1 and AMPK might mimic CR and provide broad protection against diseases of aging. Genetic studies in S. cerevisiae, C. elegans and D. melanogaster implicate several mechanisms in the regulation of lifespan. These include the insulin and insulin-like growth factor 1 (IGF-1) signaling (IIS) and mammalian target of rapamycin (mTOR) pathways which both activate the downstream effector ribosomal protein S6 kinase 1 (S6K1) (1, 2). Although the role of these pathways in mammalian aging is less clear, there is mounting evidence that IIS regulates lifespan in mice (1). Global deletion of one allele of the IGF1 receptor (Igf1r), adipose-specific deletion of the insulin receptor (Insr), global deletion of insulin receptor substrate protein 1 (Irs1) or neuron-specific deletion of Irs2 all increase mouse lifespan (1). Lifespan-extending mutations in the somatotropic axis also appear to work through attenuated IIS (3). Igf1r has also been implicated as a modulator of human longevity (4). However, the action of downstream effectors of IIS or mTOR signaling in mammalian longevity is not fully understood.S6K1 transduces anabolic signals that indicate nutritional status to regulate cell size and growth and metabolism through various mechanisms (5). These include effects on the translational machinery and on cellular energy levels through the activity of adenosine monophosphate (AMP)-activated protein kinase (AMPK) (6, 7). Furthermore, S6K1 serine phosphorylates IRS1 and IRS2 thereby decreasing insulin signaling (5). Given the key role of S6K1 in IIS and mTOR signaling, and the regulation of aging in lower organisms by mTOR, S6K, and their downstream effectors (2) we used log rank testing to evaluate differences in lifespan of wild-type (WT) and S6K1 -/-littermate mice on a C57BL/6 background (8). Data for both sexes combined showed median lifespan in S6K1 -/-mice increased by 80 days (from 862 to 942 days) or 9% relative to that of WT mice (X 2 = 10.52, p < 0.001) ( Fig. 1A and Table 1). Maximum lifespan (mean lifespan of the oldest 10% within a cohort) was also increased (1077±16 and 1175±24 days, p < 0.01 for WT and S6K1 -/-mice, respectively). Analysis of each sex separately showed that median lifespan in female S6K1 -/-mice was increased, by 153 d...

The phosphoinositide 3-kinase (PI3K) family of enzymes is recruited upon growth factor receptor activation and produces 3' phosphoinositide lipids. The lipid products of PI3K act as second messengers by binding to and activating diverse cellular target proteins. These events constitute the start of a complex signaling cascade, which ultimately results in the mediation of cellular activities such as proliferation, differentiation, chemotaxis, survival, trafficking, and glucose homeostasis. Therefore, PI3Ks play a central role in many cellular functions. The factors that determine which cellular function is mediated are complex and may be partly attributed to the diversity that exists at each level of the PI3K signaling cascade, such as the type of stimulus, the isoform of PI3K, or the nature of the second messenger lipids. Numerous studies have helped to elucidate some of the key factors that determine cell fate in the context of PI3K signaling. For example, the past two years has seen the publication of many transgenic and knockout mouse studies where either PI3K or its signaling components are deregulated. These models have helped to build a picture of the role of PI3K in physiology and indeed there have been a number of surprises. This review uses such models as a framework to build a profile of PI3K function within both the cell and the organism and focuses, in particular, on the role of PI3K in cell regulation, immunity, and development. The evidence for the role of deregulated PI3K signaling in diseases such as cancer and diabetes is reviewed.

Genetic mutations cause primary immunodeficiencies (PIDs), which predispose to infections. Here we describe Activated PI3K-δ Syndrome (APDS), a PID associated with a dominant gain-offunction mutation E1021K in the p110δ protein, the catalytic subunit of phosphoinositide 3-kinase δ (PI3Kδ), encoded by the PIK3CD gene. We found E1021K in 17 patients from seven unrelated