Phosphatidylinositol 3-kinase signaling in thymocytes: the need for stringent control.

The thymus serves as the primary site for the lifelong formation of new T lymphocytes; hence, it is essential for the maintenance of an effective immune system. Although thymocyte development has been widely studied, the mechanisms involved are incompletely defined. A comprehensive understanding of the molecular events that control regular thymocyte development will not only shed light on the physiological control of T cell differentiation but also probably provide insight into the pathophysiology of T cell immunodeficiencies, the molecular basis that underpins autoimmunity, and the mechanisms that instigate the formation of T cell lymphomas.

Protein kinase B (PKB/Akt), a key mediator of the PI3K signaling pathway.

Protein kinase B (PKB/Akt) is a serine/threonine protein kinase that created serious interest when it was revealed as a mediator of the PI3K pathway. It comprises three isoforms that play both unique and redundant roles. Upon binding to phosphatidylinositol-(3,4,5)-trisphosphate (PIP3) generated by PI3K, PKB is phosphorylated by PDK1 at T308.

Deletion of PKBalpha/Akt1 affects thymic development.

Background: The thymus constitutes the primary lymphoid organ for the majority of T cells. The phosphatidyl-inositol 3 kinase (PI3K) signaling pathway is involved in lymphoid development. Defects in single components of this pathway prevent thymocytes from progressing beyond early T cell developmental stages.

Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation.

Liver receptor homolog 1 (LRH-1) is an orphan nuclear receptor that synergizes with beta-catenin/T cell factor 4 signaling to stimulate intestinal crypt cell renewal. We evaluated here the impact of haploinsufficiency of LRH-1 on intestinal tumorigenesis by using two independent mouse models of human colon tumorigenesis. Haploinsufficiency of LRH-1 blunts intestinal tumorigenesis in the ApcMin/+ mice, a genetic model of intestinal cancer.

Synergy between LRH-1 and beta-catenin induces G1 cyclin-mediated cell proliferation.

LRH-1 is an orphan nuclear receptor predominantly expressed in tissues of endodermal origin, where it controls development and cholesterol homeostasis. We show here that LRH-1 induces cell proliferation through the concomitant induction of cyclin D1 and E1, an effect that is potentiated by its interaction with beta-catenin. Whereas beta-catenin coactivates LRH-1 on the cyclin E1 promoter, LRH-1 acts as a potent tissue-restricted coactivator of beta-catenin on the cyclin D1 promoter.

LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis.

The liver receptor homolog-1 (LRH-1; NR5A2) and steroidogenic factor-1 (SF-1; NR5A1) are two orphan members of the Ftz-F1 subfamily of nuclear receptors. LRH-1 is expressed in tissues derived from endoderm, including intestine, liver and exocrine pancreas, as well as in the ovary. In these tissues, LRH-1 plays a predominant role in development, reverse cholesterol transport, bile-acid homeostasis and steroidogenesis.

Transcription factors and nuclear receptors interact with the SWI/SNF complex through the BAF60c subunit.

Transcriptional activity relies on coregulators that modify chromatin structure or serve as bridging factors between transcription factors and the basal transcription machinery. We identified a new coregulator of peroxisome proliferator-activated receptor gamma, BRG1/Brm-associated factor of 60 kDa, subunit c2 (BAF60c2), in a yeast two-hybrid screen of a human adipose tissue cDNA library. BAF60c2 represents a new isoform of BAF60c, a component of the SWI/SNF (mating type switching/sucrose non-fermenting) chromatin remodeling complex.

Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development.

Liver receptor homolog 1 (LRH-1) and pancreatic-duodenal homeobox 1 (PDX-1) are coexpressed in the pancreas during mouse embryonic development. Analysis of the regulatory region of the human LRH-1 gene demonstrated the presence of three functional binding sites for PDX-1. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis showed that PDX-1 bound to the LRH-1 promoter, both in cultured cells in vitro and during pancreatic development in vivo.

Liver receptor homolog 1 controls the expression of carboxyl ester lipase.

The orphan nuclear receptor liver receptor homolog 1 (LRH-1) plays a central role in cholesterol homeostasis by regulating a number of hepatic and intestinal genes critical for reverse cholesterol transport and bile acid homeostasis. Herein, we describe the identification of carboxyl ester lipase (CEL) as a novel target of LRH-1 in pancreas, a tissue in which LRH-1 is abundantly expressed. In situ hybridization and gene expression studies demonstrate that both LRH-1 and CEL are co-expressed and confined to the exocrine pancreas.

Nuclear receptors and the control of metabolism.

The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR).

Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

The scavenger receptor class B type I (SR-BI), which mediates selective cellular cholesterol uptake from high-density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. The orphan nuclear receptor liver receptor homolog 1 (LRH-1) and SR-BI are co-expressed in liver and ovary, suggesting that LRH-1 might control the expression of SR-BI in these tissues. LRH-1 induces human and mouse SR-BI promoter activity by binding to an LRH-1 response element in the promoter.