Kortylewski M et al. (DEC 2005)
Nature medicine 11 12 1314--21
Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity.
The immune system can act as an extrinsic suppressor of tumors. Therefore,tumor progression depends in part on mechanisms that downmodulate intrinsic immune surveillance. Identifying these inhibitory pathways may provide promising targets to enhance antitumor immunity. Here,we show that Stat3 is constitutively activated in diverse tumor-infiltrating immune cells,and ablating Stat3 in hematopoietic cells triggers an intrinsic immune-surveillance system that inhibits tumor growth and metastasis. We observed a markedly enhanced function of dendritic cells,T cells,natural killer (NK) cells and neutrophils in tumor-bearing mice with Stat3(-/-) hematopoietic cells,and showed that tumor regression requires immune cells. Targeting Stat3 with a small-molecule drug induces T cell- and NK cell-dependent growth inhibition of established tumors otherwise resistant to direct killing by the inhibitor. Our findings show that Stat3 signaling restrains natural tumor immune surveillance and that inhibiting hematopoietic Stat3 in tumor-bearing hosts elicits multicomponent therapeutic antitumor immunity.
View Publication
产品类型：
产品号#：
18709
18709RF
产品名：
EasySep™小鼠定制正选试剂盒
RoboSep™ 小鼠定制正选试剂盒含滤芯吸头
文献
Nemeth MJ et al. (SEP 2006)
Proceedings of the National Academy of Sciences of the United States of America 103 37 13783--8
Hmgb3 regulates the balance between hematopoietic stem cell self-renewal and differentiation.
Hmgb3 is an X-linked member of a family of sequence-independent chromatin-binding proteins that is preferentially expressed in hematopoietic stem cells (HSC). Hmgb3-deficient mice (Hmgb3(-/Y)) contain normal numbers of HSCs,capable of self-renewal and hematopoietic repopulation,but fewer common lymphoid (CLP) and common myeloid progenitors (CMP). In this study,we tested the hypothesis that Hmgb3(-/Y) HSCs are biased toward self-renewal at the expense of progenitor production. Wild-type and Hmgb3(-/Y) CLPs and CMPs proliferate and differentiate equally in vitro,indicating that CLP and CMP function normally in Hmgb3(-/Y) mice. Hmgb3(-/Y) HSCs exhibit constitutive activation of the canonical Wnt signaling pathway,which regulates stem cell self-renewal. Increased Wnt signaling in Hmgb3(-/Y) HSCs corresponds to increased expression of Dvl1,a positive regulator of the canonical Wnt pathway. To induce hematopoietic stress and a subsequent response from HSCs,we treated Hmgb3(-/Y) mice with 5-fluorouracil. Hmgb3(-/Y) mice exhibit a faster recovery of functional HSCs after administration of 5-fluorouracil compared with wild-type mice,which may be due to the increased Wnt signaling. Furthermore,the recovery of HSC number in Hmgb3(-/Y) mice occurs more rapidly than CLP and CMP recovery. From these data,we propose a model in which Hmgb3 is required for the proper balance between HSC self-renewal and differentiation.
View Publication
产品类型：
产品号#：
03630
03434
03444
09600
09650
产品名：
MethoCult™M3630
MethoCult™GF M3434
MethoCult™GF M3434
StemSpan™ SFEM
StemSpan™ SFEM
文献
Muraille E et al. (SEP 1999)
The Biochemical journal 342 Pt 3 697--705
Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells.
The termination of activation signals is a critical step in the control of the immune response; perturbation of inhibitory feedback pathways results in profound immune defects culminating in autoimmunity and overwhelming inflammation. FcgammaRIIB receptor is a well described inhibitory receptor. The ligation of B-cell receptor (BCR) and FcgammaRIIB leads to the inhibition of B-cell activation. Numerous studies have demonstrated that the SH2-domain-containing inositol 5-phosphatase SHIP (referred hereto as SHIP-1) is essential in this process. The cDNA encoding a second SH2-domain-containing inositol 5-phosphatase,SHIP-2,has been cloned [Pesesse,Deleu,De Smedt,Drayer and Erneux (1997) Biochem. Biophys. Res. Commun. 239,697-700]. Here we report the distribution of SHIP-2 in mouse tissues: a Western blot analysis of mouse tissues reveals that SHIP-2 is expressed in both haemopoietic and non-haemopoietic cells. In addition to T-cell and B-cell lines,spleen,thymus and lung are shown to coexpress SHIP-1 and SHIP-2. Moreover,SHIP-2 is detected in fibroblasts,heart and different brain areas. SHIP-2 shows a maximal tyrosine phosphorylation and association to Shc after ligation of BCR to FcgammaRIIB but not after stimulation of BCR alone. Our results therefore suggest a possible role for SHIP-2 in the negative regulation of immunocompetent cells.
View Publication
Megakaryoblastic leukemia 1 (MKL1),identified as part of the t(1;22) translocation specific to acute megakaryoblastic leukemia,is highly expressed in differentiated muscle cells and promotes muscle differentiation by activating serum response factor (SRF). Here we show that Mkl1 expression is up-regulated during murine megakaryocytic differentiation and that enforced overexpression of MKL1 enhances megakaryocytic differentiation. When the human erythroleukemia (HEL) cell line is induced to differentiate with 12-O-tetradecanoylphorbol 13-acetate,overexpression of MKL1 results in an increased number of megakaryocytes with a concurrent increase in ploidy. MKL1 overexpression also promotes megakaryocytic differentiation of primary human CD34(+) cells cultured in the presence of thrombopoietin. The effect of MKL1 is abrogated when SRF is knocked down,suggesting that MKL1 acts through SRF. Consistent with these findings in human cells,knockout of Mkl1 in mice leads to reduced platelet counts in peripheral blood,and reduced ploidy in bone marrow megakaryocytes. In conclusion,MKL1 promotes physiologic maturation of human and murine megakaryocytes.
View Publication
Huang S and Houghton PJ (AUG 2003)
Current opinion in pharmacology 3 4 371--7
Targeting mTOR signaling for cancer therapy.
The mammalian target of rapamycin (mTOR),an atypical serine/threonine kinase,plays a central role in the regulation of cell proliferation,growth,differentiation,migration and survival. Dysregulation of mTOR signaling occurs in diverse human tumours,and can confer higher susceptibility to inhibitors of mTOR. Rapamycin and its derivatives,CCI-779 and RAD001 (designated rapamycins),specifically inhibit the function of mTOR,leading to inactivation of ribosomal S6K1 and inhibition of cap-dependent translation initiation through the 4E-BP1/eIF4E pathway. The overall effect is an accumulation of cells in the G1 phase of the cell-cycle,and potential apoptosis. Preclinical studies indicate that rapamycins are potent inhibitors of the proliferation of numerous tumour cell lines in culture and of murine syngeneic tumour models or human xenografts. RAD001 and CCI-779 are in phase I and II trials,respectively,as anti-cancer agents. These trials have demonstrated promising anti-cancer activity and relatively mild side effects of CCI-779. Emerging results suggest that inhibition of mTOR signaling can be exploited as a potential tumour-selective therapeutic strategy.
View Publication
The endothelial antigen ESAM marks primitive hematopoietic progenitors throughout life in mice.
Although recent advances have enabled hematopoietic stem cells (HSCs) to be enriched to near purity,more information about their characteristics will improve our understanding of their development and stage-related functions. Here,using microarray technology,we identified endothelial cell-selective adhesion molecule (ESAM) as a novel marker for murine HSCs in fetal liver. Esam was expressed at high levels within a Rag1(-) c-kit(Hi) Sca1(+) HSC-enriched fraction,but sharply down-regulated with activation of the Rag1 locus,a valid marker for the most primitive lymphoid progenitors in E14.5 liver. The HSC-enriched fraction could be subdivided into 2 on the basis of ESAM levels. Among endothelial antigens on hematopoietic progenitors,ESAM expression showed intimate correlation with HSC activity. The ESAM(Hi) population was highly enriched for multipotent myeloid-erythroid progenitors and primitive progenitors with lymphopoietic activity,and exclusively reconstituted long-term lymphohematopoiesis in lethally irradiated recipients. Tie2(+) c-kit(+) lymphohematopoietic cells in the E9.5-10.5 aorta-gonad-mesonephros region also expressed high levels of ESAM. Furthermore,ESAM was detected on primitive hematopoietic progenitors in adult bone marrow. Interestingly,ESAM expression in the HSC-enriched fraction was up-regulated in aged mice. We conclude that ESAM marks HSC in murine fetal liver and will facilitate studies of hematopoiesis throughout life.
View Publication
EasySep™小鼠TIL（CD45）正选试剂盒
文献
产品手册Small Molecules for Stem Cell Research
科学海报Manipulation of the Standard CFU-GM Assay Targeted Screening of Hematopoietic Myeloid Progenitors
技术公告Air-Liquid Interface Culture for Respiratory Research
