[Keywords: YAP; Lats; Mst; contact inhibition; NF2; Hippo] Supplemental material is available at http://www.genesdev.org.
Patten recognition receptors, which recognize pathogens or components of injured cells (danger), trigger activation of the innate immune system. Whether and how the host distinguishes between danger- versus pathogen-associated molecular patterns remains unresolved. We report that CD24-deficient mice exhibit increased susceptibility to danger- but not pathogen-associated molecular patterns. CD24 associates with high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70) and heat shock protein 90 (HSP90), negatively regulates their stimulatory activity and inhibits nuclear factor-kappa B (NF-κB) activation. This occurs at least in part through CD24 association with Siglec-10 in humans or Siglec-G in mice. Our results reveal that the CD24-Siglec G pathway protects the host against a lethal response to pathological cell death and discriminates danger- versus pathogen-associated molecular patterns.
Age-related declines in hematopoietic stem cell (HSC) function may contribute to anemia, poor response to vaccination, and tumorigenesis. Here, we show that mammalian target of rapamycin (mTOR) activity is increased in HSCs from old mice compared to those from young mice. mTOR activation through conditional deletion of Tsc1 in the HSC of young mice mimicked the phenotype of HSC from aged mice in various ways. These included increased abundance of the mRNA encoding the CDK inhibitors p16Ink4a, p19Arf, and p21Cip1, a relative decrease in lymphopoiesis, and impaired capacity to reconstitute the hematopoietic system. In the old mice, rapamycin increased the life span, restored the self renewal and hematopoiesis of HSC, and enabled effective vaccination against a lethal challenge with influenza virus. Together, our data implicate mTOR signaling in HSC aging and demonstrate the potential of mTOR inhibitors for restoring hematopoiesis in the elderly.
A long-standing but poorly understood observation in stem cell biology is that the quiescence of the adult stem cells associates with their longterm functions ( 1 -6 ). The molecular pathway that keeps them in quiescence is largely obscure, although recent studies have implicated stem cell niches ( 4 ) and cell-intrinsic functions of p21 ( 5 ) and Pten ( 6 ) in this process. The signifi cance of quiescence in stem cell function is bolstered as genetic disruption of its quiescence almost invariably inactivates the hematopoietic stem cell (HSC) function ( 4 -6 ). Nevertheless, it is largely unclear how an active metabolism is incompatible with a normal HSC function.In addition to cell-intrinsic factors, accumulating data demonstrated that residence of adult HSCs in the BM niches is essential for their quiescence and long-term functions ( 7 -9 ). Because exposure to high levels of oxygen damages the functions of HSCs ( 10 -15 ), it has been proposed that hypoxia is important for HSC functions. However, the underlying molecular mechanism of how hypoxia maintains the stemness is unknown.In Drosophila and in vitro -cultured mammalian cells, hypoxia activates tuberous sclerosis complex (TSC), which can inhibit the target of rapamycin (TOR), through REDD1 and AMP-activated protein kinase ( 16 -20 ). Whether this pathway operates in the HSCs has yet to be tested.The mammalian TOR (mTOR) pathway has emerged as a key regulator for cellular metabolism. Accumulating data have demonstrated that mTOR regulates several important cellular functions, including protein synthesis, autophagy, endocytosis and nutrient uptake ( 21 ). An increased mTOR activity results in increased cellular growth and nonmalignant growth of cells in solid organs ( 22,23 The tuberous sclerosis complex (TSC) -mammalian target of rapamycin (mTOR) pathway is a key regulator of cellular metabolism. We used conditional deletion of Tsc1 to address how quiescence is associated with the function of hematopoietic stem cells (HSCs). We demonstrate that Tsc1 deletion in the HSCs drives them from quiescence into rapid cycling, with increased mitochondrial biogenesis and elevated levels of reactive oxygen species (ROS). Importantly, this deletion dramatically reduced both hematopoiesis and self-renewal of HSCs, as revealed by serial and competitive bone marrow transplantation. In vivo treatment with an ROS antagonist restored HSC numbers and functions. These data demonstrated that the TSC -mTOR pathway maintains the quiescence and function of HSCs by repressing ROS production. The detrimental effect of up-regulated ROS in metabolically active HSCs may explain the well-documented association between quiescence and the " stemness " of HSCs.
The X-linked Foxp3 is a member of the forkhead/winged helix transcription factor family. Germline mutations cause lethal autoimmune diseases in males. Serendipitously, we observed that female mice heterozygous for the "scurfin" mutation of the Foxp3 gene (Foxp3(sf/+)) developed cancer at a high rate. The majority of the cancers were mammary carcinomas in which the wild-type Foxp3 allele was inactivated and HER-2/ErbB2 was overexpressed. Foxp3 bound and repressed the HER-2/ErbB2 promoter. Deletion, functionally significant somatic mutations, and downregulation of the FOXP3 gene were commonly found in human breast cancer samples and correlated significantly with HER-2/ErbB2 overexpression, regardless of the status of HER-2 amplification. Our data demonstrate that FOXP3 is an X-linked breast cancer suppressor gene and an important regulator of the HER-2/ErbB2 oncogene.
Molecular targeting of cancer stem cells has therapeutic potential for efficient treatment of cancer although relatively few specific targets have so far been identified. Hypoxia-inducible factor was recently shown to regulate tumorigenic capacity of glioma stem cells under hypoxic condition. Surprisingly, we found that, under normoxia, HIF1α signaling was selectively activated in the stem cells of mouse lymphoma and human acute myeloid leukemia (AML). HIF1a ShRNA and HIF inhibitors abrogated the colony forming unit activity of mouse lymphoma and human AML CSCs. Importantly, the HIF inhibitor echinomycin efficiently eradicated mouse lymphoma and serially transplantable human AML in xenogeneic model by preferential elimination of CSCs. HIF1α maintains mouse lymphoma CSCs by repressing a negative feedback loop in the Notch pathway. Taken together, our results demonstrate an essential function of HIF1α-Notch interaction in maintaining CSCs and provide an effective approach to target CSCs for therapy of hematological malignancies.
Despite clear epidemiological and genetic evidence for X-linked prostate cancer risk, all prostate cancer genes identified are autosomal. Here we report somatic inactivating mutations and deletion of the X-linked FOXP3 gene residing at Xp11.23 in human prostate cancer. Lineage-specific ablation of FoxP3 in the mouse prostate epithelial cells leads to prostate hyperplasia and prostate intraepithelial neoplasia. In both normal and malignant prostate tissues, FOXP3 is both necessary and sufficient to transcriptionally repress cMYC, the most commonly over-expressed oncogene in prostate cancer as well as among the aggregates of other cancers. FOXP3 is an X-linked prostate tumor suppressor in the male. Since the male has only one X chromosome, our data represents a paradigm of “single-genetic-hit” inactivation-mediated carcinogenesis.
Central tolerance is established through negative selection of self-reactive thymocytes and the induction of T-regulatory cells (T R s). The role of thymic dendritic cells (TDCs) in these processes has not been clearly determined. In this study, we demonstrate that in vivo , TDCs not only play a role in negative selection but in the induction of T R s. TDCs include two conventional dendritic cell (DC) subtypes, CD8 lo Sirpα hi/+ (CD8 lo Sirpα + ) and CD8 hi Sirpα lo/− (CD8 lo Sirpα − ), which have different origins. We found that the CD8 hi Sirpα + DCs represent a conventional DC subset that originates from the blood and migrates into the thymus. Moreover, we show that the CD8 lo Sirpα + DCs demonstrate a superior capacity to induce T R s in vitro . Finally, using a thymic transplantation system, we demonstrate that the DCs in the periphery can migrate into the thymus, where they efficiently induce T R generation and negative selection.
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