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1
Bardin, Sylvie D., Ralf T. Voegele, and Turlough M. Finan. "Phosphate Assimilation in Rhizobium(Sinorhizobium) meliloti: Identification of apit-Like Gene." Journal of Bacteriology 180, no. 16 (August 15, 1998): 4219–26. http://dx.doi.org/10.1128/jb.180.16.4219-4226.1998.
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ABSTRACT Rhizobium meliloti mutants defective in thephoCDET-encoded phosphate transport system form root nodules on alfalfa plants that fail to fix nitrogen (Fix−). We have previously reported that two classes of second-site mutations can suppress the Fix− phenotype ofphoCDET mutants to Fix+. Here we show that one of these suppressor loci (sfx1) contains two genes, orfA and pit, which appear to form an operon transcribed in the order orfA-pit. The Pit protein is homologous to various phosphate transporters, and we present evidence that three suppressor mutations arose from a single thymidine deletion in a hepta-thymidine sequence centered 54 nucleotides upstream of the orfA transcription start site. This mutation increased the level of orfA-pit transcription. These data, together with previous biochemical evidence, show that theorfA-pit genes encode a Pi transport system that is expressed in wild-type cells grown with excess Pibut repressed in cells under conditions of Pi limitation. In phoCDET mutant cells, orfA-pitexpression is repressed, but this repression is alleviated by the second-site suppressor mutations. Suppression increasesorfA-pit expression compensating for the deficiencies in phosphate assimilation and symbiosis of the phoCDETmutants.
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Powers, Jason G., Tim L. Sit, Feng Qu, T. Jack Morris, Kook-Hyung Kim, and Steven A. Lommel. "A Versatile Assay for the Identification of RNA Silencing Suppressors Based on Complementation of Viral Movement." Molecular Plant-Microbe Interactions® 21, no. 7 (July 2008): 879–90. http://dx.doi.org/10.1094/mpmi-21-7-0879.
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The cell-to-cell movement of Turnip crinkle virus (TCV) in Nicotiana benthamiana requires the presence of its coat protein (CP), a known suppressor of RNA silencing. RNA transcripts of a TCV construct containing a reporter gene (green fluorescent protein) (TCV-sGFP) in place of the CP open reading frame generated foci of three to five cells. TCV CP delivered in trans by Agrobacterium tumefaciens infiltration potentiated movement of TCV-sGFP and increased foci diameter, on average, by a factor of four. Deletion of the TCV movement proteins in TCV-sGFP (construct TCVΔ92-sGFP) abolished the movement complementation ability of TCV CP. Other known suppressors of RNA silencing from a wide spectrum of viruses also complemented the movement of TCV-sGFP when delivered in trans by Agrobacterium tumefaciens. These include suppressors from nonplant viruses with no known plant movement function, demonstrating that this assay is based solely on RNA silencing suppression. While the TCV-sGFP construct is primarily used as an infectious RNA transcript, it was also subcloned for direct expression from Agrobacterium tumefaciens for simple quantification of suppressor activity based on fluorescence levels in whole leaves. Thus, this system provides the flexibility to assay for suppressor activity in either the cytoplasm or nucleus, depending on the construct employed.
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Bedke, Tanja, Sarah Lurati, Claudia Stuehler, Nina Khanna, Hermann Einsele, and Max S. Topp. "Identification and Characterization of Human Aspergillus Fumigatus-Specific Tr1-(Like) Cells." Blood 118, no. 21 (November 18, 2011): 181. http://dx.doi.org/10.1182/blood.v118.21.181.181.
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Abstract Abstract 181 Introduction: The ubiquitous mold Aspergillus fumigatus (A. fumigatus) induces two forms of pathogenesis: invasive aspergillosis in neutropenic patients and allergic aspergillosis in patients with chronic obstructive lung disease as well as in immunosuppressed patients. Mouse models of aspergillosis suggest that not only effector T cells (Teff) but also regulatory T cells (Treg) play a crucial role for the regulation of a protective T cell-mediated immunity to A. fumigatus. However, it is little-known about the involvement of Treg during A. fumigatus infection in humans. In order to develop new therapeutical strategies for the treatment of aspergillosis this project aims to understand the influence of regulatory T cells on A. fumigatus infection in humans. Material/Methods: A. fumigatus-specific CD4+ T cell clones were established from PBMC of healthy donors. Based on this clone pool Treg clones were identified due to their inability to proliferate in the absence of costimulation assessed by 3[H]-TdR incorporation as well as their Ag-specific cytokine production and phenotype determined by flow cytometry. Treg function was analyzed by their ability to suppress proliferation of autologous CD4+ T cells using CFSE dilution. Results: We identified A. fumigatus-specific T cell clones that exhibited marginal detectable proliferation after restimulation with immobilized anti-CD3 mAb in the absence of costimulation. However, these T cell clones vigorously proliferated in response to restimulation with their cognate antigen. A more detailed characterization showed that these suppressor T cell clones produced high amounts of IL-10 and moderate levels of IFN-gamma upon Ag-specific restimulation and expressed low amounts of Foxp3 but not Helios, a transcription factor that had recently been linked to natural occurring Treg. Most importantly, these T cell clones suppressed Ag-specific expansion of CD4+ Teff. This effect was contact-independent since suppression of Ag-specific CD4+ T cell expansion detected in transwell experiments was comparable to cocultures that enabled cellular-contact. Furthermore, anti-CD3/CD28-induced proliferation of naïve CD4+ T cells was not reduced in the presence of culture supernatants obtained from suppressor T cell clones after their antigen-specific restimulation in the absence of DCs. Conclusions: We identified for the first time A. fumigatus-specific CD4+ T cell clones with a Tr1(-like) IL-10+IFN-gamma+Foxp3lowHelios− phenotype. These cells suppressed expansion of A. fumigatus-specific Teff in an Ag-specific manner mediated by soluble factors released from Tr1(-like) cell clones. Since these factors did not affect CD4+ T cell proliferation in the absence of DCs our data suggest, that Tr1(-like) cell clones rather negatively regulate the stimulatory capacity of DCs leading to a reduced expansion of Ag-specific CD4+ T cells. Therefore these Tr1(-like) cells might play a protective role during A. fumigatus infection in humans. Thus, adoptive transfer of A. fumigatus-specific Treg could be useful to enhance protective immunity in patients with chronic A. fumigatus infection. Disclosures: Topp: Micromet: Consultancy, Honoraria.
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Benni, Mei Li, and Lenore Neigeborn. "Identification of a New Class of Negartive Regulators Affecting Sporulation-Specific Gene Expression in Yeast." Genetics 147, no. 3 (November 1, 1997): 1351–66. http://dx.doi.org/10.1093/genetics/147.3.1351.
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We characterized two yeast loci, MDS3 and PMD1, that negatively regulate sporulation. Initiation of sporulation is mediated by the meiotic activator IME1, which relies on MCK1 for maximal expression. We isolated the MDS3-1 allele (encoding a truncated form of Mds3p) as a suppressor that restores IME1 expression in mck1 mutants. mds3 null mutations confer similar suppression phenotypes as MDS3-1, indicating that Mds3p is a negative regulator of sporulation and the MDS3-1 allele confers a dominant-negative phenotype. PMD1 is predicted to encode a protein sharing significant similarity with Mds3p. mds3 pmd1 double mutants are better suppressors of mck1 than is either single mutant, indicating that Mds3p and Pmd1p function synergistically. Northern blot analysis revealed that suppression is due to increased IME1 transcript accumulation. The roles of Mds3p and Pmd1p are not restricted to the MCK1 pathway because mds3 pmd1 mutations also suppress IME1 expression defects associated with MCK1-independent sporulation mutants. Furthermore, mds3 pmdl mutants express significant levels of IME1 even in vegetative cells and this unscheduled expression results in premature sporulation. These phenotypes, and interactions with RAS2-Val19 suggest that unscheduled derepression of IME1 is probably due to a defect in recognition of nutritional status.
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He, B., Y. Chiba, H. Li, S. de Vega, K. Tanaka, K. Yoshizaki, M. Ishijima, et al. "Identification of the Novel Tooth-Specific Transcription Factor AmeloD." Journal of Dental Research 98, no. 2 (November 14, 2018): 234–41. http://dx.doi.org/10.1177/0022034518808254.
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Basic-helix-loop-helix (bHLH) transcription factors play an important role in various organs’ development; however, a tooth-specific bHLH factor has not been reported. In this study, we identified a novel tooth-specific bHLH transcription factor, which we named AmeloD, by screening a tooth germ complementary DNA (cDNA) library using a yeast 2-hybrid system. AmeloD was mapped onto the mouse chromosome 1q32. Phylogenetic analysis showed that AmeloD belongs to the achaete-scute complex-like ( ASCL) gene family and is a homologue of ASCL5. AmeloD was uniquely expressed in the inner enamel epithelium (IEE), but its expression was suppressed after IEE cell differentiation into ameloblasts. Furthermore, AmeloD expression showed an inverse expression pattern with the epithelial cell-specific cell–cell adhesion molecule E-cadherin in the dental epithelium. Overexpression of AmeloD in dental epithelial cell line CLDE cells resulted in E-cadherin suppression. We found that AmeloD bound to E-box cis-regulatory elements in the proximal promoter region of the E-cadherin gene. These results reveal that AmeloD functions as a suppressor of E-cadherin transcription in IEE cells. Our study demonstrated that AmeloD is a novel tooth-specific bHLH transcription factor that may regulate tooth development through the suppression of E-cadherin in IEE cells.
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Movahedi, Kiavash, Martin Guilliams, Jan Van den Bossche, Rafael Van den Bergh, Conny Gysemans, Alain Beschin, Patrick De Baetselier, and Jo A. Van Ginderachter. "Identification of discrete tumor-induced myeloid-derived suppressor cell subpopulations with distinct T cell–suppressive activity." Blood 111, no. 8 (April 15, 2008): 4233–44. http://dx.doi.org/10.1182/blood-2007-07-099226.
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Abstract The induction of CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) is an important immune-evading mechanism used by tumors. However, the exact nature and function of MDSCs remain elusive, especially because they constitute a heterogeneous population that has not yet been clearly defined. Here, we identified 2 distinct MDSC subfractions with clear morphologic, molecular, and functional differences. These fractions consisted of either mononuclear cells (MO-MDSCs), resembling inflammatory monocytes, or low-density polymorphonuclear cells (PMN-MDSCs), akin to immature neutrophils. Interestingly, both MO-MDSCs and PMN-MDSCs suppressed antigen-specific T-cell responses, albeit using distinct effector molecules and signaling pathways. Blocking IFN-γ or disrupting STAT1 partially impaired suppression by MO-MDSCs, for which nitric oxide (NO) was one of the mediators. In contrast, while IFN-γ was strictly required for the suppressor function of PMN-MDSCs, this did not rely on STAT1 signaling or NO production. Finally, MO-MDSCs were shown to be potential precursors of highly antiproliferative NO-producing mature macrophages. However, distinct tumors differentially regulated this inherent MO-MDSC differentiation program, indicating that this phenomenon was tumor driven. Overall, our data refine tumor-induced MDSC functions by uncovering mechanistically distinct MDSC subpopulations, potentially relevant for MDSC-targeted therapies.
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Anger, Natalia, and Joanna Rossowska. "Myeloid-derived suppressor cells as a target for anticancer therapy." Postępy Higieny i Medycyny Doświadczalnej 72 (December 31, 2018): 1179–98. http://dx.doi.org/10.5604/01.3001.0012.8267.
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Myeloid-derived suppressor cells are heterogenic immature myeloid cells, which possess suppressor activity and play an important role in both, tumor progression and metastasis. The accumulation of MDSCs is induced primarily by factors that are secreted by the tumor microenvironment, which disturb myelopoiesis that occurs in the bone marrow and enables the migration of immature myeloid cells into the tumor. MDSCs promote tumor growth by inhibiting the activity of immunocompetent cells, as well as by activating non-immunological processes, such as tumor angiogenesis, the degradation of extracellular matrix and the formation of premetastatic niche. Due to their significant impact on the development of cancer, MDSCs became clinically relevant in tumor diagnostics. In recent years, various therapeutic strategies were developed in order to inhibit the proliferation, accumulation or suppressor activity of MDSCs, as well as to render the differentiation or total depletion of these cells. The proposed therapies often combine factors that reduce MDSCs suppression with conventional chemotherapy or with immune checkpoints inhibitors. In this review, we describe the current state of knowledge about factors that enable the accumulation of MDSCs, methods of phenotypic identification of these cells, as well as the mechanisms of suppression used by them. Moreover, we provide insight into the therapeutic approaches, which aim to restore the reactivity of the immune system by reducing the suppressor effects of MDSCs.
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Kansa, Geoffrey S., and Edgar G. Engleman. "Phenotypic identification of suppressor-effector, suppressor-amplifier and suppressor-inducer T cells of B cell differentiation in man." European Journal of Immunology 17, no. 4 (1987): 453–57. http://dx.doi.org/10.1002/eji.1830170403.
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Zimring, James C., and Judith A. Kapp. "Identification and Characterization of CD8+ Suppressor T Cells." Immunologic Research 29, no. 1-3 (2004): 303–12. http://dx.doi.org/10.1385/ir:29:1-3:303.
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Blanchard, Thomas G., Steven J. Czinn, Vivekjyoti Banerjee, Neha Sharda, Andrea C. Bafford, Fahad Mubariz, Dennis Morozov, Antonino Passaniti, Hafiz Ahmed, and Aditi Banerjee. "Identification of Cross Talk between FoxM1 and RASSF1A as a Therapeutic Target of Colon Cancer." Cancers 11, no. 2 (February 8, 2019): 199. http://dx.doi.org/10.3390/cancers11020199.
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Metastatic colorectal cancer (mCRC) is characterized by the expression of cellular oncogenes, the loss of tumor suppressor gene function. Therefore, identifying integrated signaling between onco-suppressor genes may facilitate the development of effective therapy for mCRC. To investigate these pathways we utilized cell lines and patient derived organoid models for analysis of gene/protein expression, gene silencing, overexpression, and immunohistochemical analyses. An inverse relationship in expression of oncogenic FoxM1 and tumor suppressor RASSF1A was observed in various stages of CRC. This inverse correlation was also observed in mCRC cells lines (T84, Colo 205) treated with Akt inhibitor. Inhibition of FoxM1 expression in mCRC cells as well as in our ex vivo model resulted in increased RASSF1A expression. Reduced levels of RASSF1A expression were found in normal cells (RWPE-1, HBEpc, MCF10A, EC) stimulated with exogenous VEGF165. Downregulation of FoxM1 also coincided with increased YAP phosphorylation, indicative of tumor suppression. Conversely, downregulation of RASSF1A coincided with FoxM1 overexpression. These studies have identified for the first time an integrated signaling pathway between FoxM1 and RASSF1A in mCRC progression, which may facilitate the development of novel therapeutic options for advanced colon cancer therapy.
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Du, Quansheng, Dana Lehavi, Ouriel Faktor, Yipeng Qi, and Nor Chejanovsky. "Isolation of an Apoptosis Suppressor Gene of theSpodoptera littoralis Nucleopolyhedrovirus." Journal of Virology 73, no. 2 (February 1, 1999): 1278–85. http://dx.doi.org/10.1128/jvi.73.2.1278-1285.1999.
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ABSTRACT Spodoptera frugiperda SF9 cells infected with mutants of the Autographa californica nucleopolyhedrovirus (AcMNPV) which lack a functional p35 gene undergo apoptosis, aborting the viral infection. The Spodoptera littoralis nucleopolyhedrovirus (SlNPV) was able to suppress apoptosis triggered by vΔP35K/pol+, an AcMNPVp35 null mutant. To identify the putative apoptotic suppressor gene of SlNPV, overlapping cosmid clones representing the entire SlNPV genome were individually cotransfected along with genomic DNA of vΔP35K/pol+. Using this complementation assay, we isolated a SlNPV DNA fragment that was able to rescue the vΔP35K/pol+ infection in SF9 cells. By further subcloning and rescue, we identified a novel SlNPV gene, Slp49. TheSlp49 sequence predicted a 49-kDa polypeptide with about 48.8% identity to the AcMNPV apoptotic suppressor P35. SLP49 displays a potential recognition site, TVTDG, for cleavage by death caspases. Recombinant AcMNPVs deficient inp35 bearing the Slp49 gene did not induce apoptosis and showed successful productive infections in SF9 cells, indicating that Slp49 is a functional homologue ofp35. A 1.5-kbp Slp49-specific transcript was identified in SF9 cells infected with SlNPV or with vAc496, a vΔP35K/pol+-recombinant bearing Slp49. The discovery of Slp49 contributes to the identification of important functional motifs conserved in p35-like apoptotic suppressors and to the future isolation of p35-like genes from other baculoviruses.
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Kawamata, Norihiko, Takayuki Saitoh, Sakura Sakajiri, and Phillip H. Koeffler. "Identification of Candidate Tumor Suppressor Genes Silenced Epigenetically in Mantle Cell Lymphoma." Blood 106, no. 11 (November 16, 2005): 3001. http://dx.doi.org/10.1182/blood.v106.11.3001.3001.
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Abstract Many tumor suppressor genes are silenced by epigenetic mechanisms in human cancers, including mantle cell lymphoma (MCL). In this study, we have used a variety of research tools to screen for genes that are epigenetically silenced in MCL. Changes in the global gene expression profile of the MCL cell line, Jeko1, were analyzed after treatment with the combination of the demethylating agent, 5-aza-2′-deoxycytidine, and the histone deacetylase inhibitor, suberoyl anilide bishydroxamide, by DNA microarray technique. By screening over 22,000 genes, we identified 26 candidate tumor suppressor genes, expression of which were enhanced by the treatment, in the MCL line. Basal expression of these 26 genes were low in Jeko1 cells. The treatment enhanced the expression more than 2 folds and the enhancement was also confirmed by real-time PCR. Methylation status of these 26 genes were examined by bisulfite sequencing and/or combined bisulfite and restriction enzyme digestion assay in Jeko1 cells. We found hypermethylation of a CpG island in the middle of the INPP5F gene. We also found the hypermethylation of that region of INPP5F in normal peripheral blood. We also examined expression levels of these 26 genes in normal mantle cells by real-time PCR and found only 11 genes showed high levels of transcription in laser-dissected normal mantle cells. We examined expression of these 11 genes in eight MCL clinical samples by real-time PCR and found that only three genes, INPP5F, DUSP10 and FGD2 showed very low expression levels. We conclude that expression of INPP5F, DUSP10 and FGD2 genes were suppressed in MCL cells although the expression of these genes are high in normal mantle cells. INPP5F is a inositol phosphatase and could be involved in PI3K pathway. DUSP10 is a dual specific phosphatase and could be involved in JNK pathway. FGD2 is a RAS-GAP gene and could be involved in RAS pathway. These three genes may be candidate tumor suppressor genes in MCL and further functional analysis is ongoing.
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Kass, L. "Identification of lymphocyte subpopulations with a polymethine dye." Journal of Histochemistry & Cytochemistry 36, no. 7 (July 1988): 711–15. http://dx.doi.org/10.1177/36.7.2454984.
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Using the polymethine dye p-ethoxyphenyl-p-aminostyryl-1,3,3-trimethyl-3H-indolium chloride as an aqueous stain applied to specimens of peripheral blood or buffy coat fixed in FAA fixative, differential coloration of leukocytes was achieved using darkfield illumination. Neutrophils stained dark maroon and contained green granules, eosinophils contained bright blue granules, basophils revealed yellow and pink granules, and monocytes stained green with green and yellow vacuoles. In studies of purified lymphocyte subpopulations obtained in a cell sorter, T-helper cells stained red, T-suppressor cells were yellow orange, B-cells appeared yellow and often contained yellow annular structures in the cytoplasm, and natural killer (NK) cells stained green and contained large green granules. As a rapid screening technique for identification of T-helper and T-suppressor cells and their ratios in health and disease, the new polymethine stain may complement the more complex monoclonal antibody techniques for identification of these cells.
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HALWANI, FAWAZ, RONALD D. GUTTMANN, HÉLÈNE STE.-CROIX, and GERALD J. PRUDʼHOMME. "IDENTIFICATION OF NATURAL SUPPRESSOR CELLS IN LONG-TERM RENAL ALLOGRAFT RECIPIENTS." Transplantation 54, no. 6 (December 1992): 973–77. http://dx.doi.org/10.1097/00007890-199212000-00006.
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James, P., and B. D. Hall. "ret1-1, a yeast mutant affecting transcription termination by RNA polymerase III." Genetics 125, no. 2 (June 1, 1990): 293–303. http://dx.doi.org/10.1093/genetics/125.2.293.
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Abstract In eukaryotes, extended tracts of T residues are known to signal the termination of RNA polymerase III transcription. However, it is not understood how the transcription complex interacts with this signal. We have developed a selection system in yeast that uses ochre suppressors weakened by altered transcription termination signals to identify mutations in the proteins involved in termination of transcription by RNA polymerase III. Over 7600 suppression-plus yeast mutants were selected and screened, leading to the identification of one whose effect is mediated transcriptionally. The ret1-1 mutation arose in conjunction with multiple rare events, including uninduced sporulation, gene amplification, and mutation. In vitro transcription extracts from ret1-1 cells terminate less efficiently at weak transcription termination signals than those from RET1 cells, using a variety of tRNA templates. In vivo this reduced termination efficiency can lead to either an increase or a further decrease in suppressor strength, depending on the location of the altered termination signal present in the suppressor tRNA gene. Fractionation of in vitro transcription extracts and purification of RNA polymerase III has shown that the mutant effect is mediated by highly purified polymerase in a reconstituted system.
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Bryant, Andrew, Borna Mehrad, Todd Brusko, James West, and Lyle Moldawer. "Myeloid-Derived Suppressor Cells and Pulmonary Hypertension." International Journal of Molecular Sciences 19, no. 8 (August 3, 2018): 2277. http://dx.doi.org/10.3390/ijms19082277.
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Myeloid–derived suppressor cells (MDSCs) comprised a heterogeneous subset of bone marrow–derived myeloid cells, best studied in cancer research, that are increasingly implicated in the pathogenesis of pulmonary vascular remodeling and the development of pulmonary hypertension. Stem cell transplantation represents one extreme interventional strategy for ablating the myeloid compartment but poses a number of translational challenges. There remains an outstanding need for additional therapeutic targets to impact MDSC function, including the potential to alter interactions with innate and adaptive immune subsets, or alternatively, alter trafficking receptors, metabolic pathways, and transcription factor signaling with readily available and safe drugs. In this review, we summarize the current literature on the role of myeloid cells in the development of pulmonary hypertension, first in pulmonary circulation changes associated with myelodysplastic syndromes, and then by examining intrinsic myeloid cell changes that contribute to disease progression in pulmonary hypertension. We then outline several tractable targets and pathways relevant to pulmonary hypertension via MDSC regulation. Identifying these MDSC-regulated effectors is part of an ongoing effort to impact the field of pulmonary hypertension research through identification of myeloid compartment-specific therapeutic applications in the treatment of pulmonary vasculopathies.
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Lee, Hansoo, Donghwa Kim, Han C. Dan, Eric L. Wu, Tatiana M. Gritsko, Chuanhai Cao, Santo V. Nicosia, et al. "Identification and Characterization of Putative Tumor Suppressor NGB, a GTP-Binding Protein That Interacts with the Neurofibromatosis 2 Protein." Molecular and Cellular Biology 27, no. 6 (January 8, 2007): 2103–19. http://dx.doi.org/10.1128/mcb.00572-06.
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ABSTRACT Mutations of the neurofibromatosis 2 (NF2) tumor suppressor gene have frequently been detected not only in schwannomas and other central nervous system tumors of NF2 patients but also in their sporadic counterparts and malignant tumors unrelated to the NF2 syndrome such as malignant mesothelioma, indicating a broader role for the NF2 gene in human tumorigenesis. However, the mechanisms by which the NF2 product, merlin or schwannomin, is regulated and controls cell proliferation remain elusive. Here, we identify a novel GTP-binding protein, dubbed NGB (referring to NF2-associated GTP binding protein), which binds to merlin. NGB is highly conserved between Saccharomyces cerevisiae, Caenorhabditis elegans, and human cells, and its GTP-binding region is very similar to those found in R-ras and Rap2. However, ectopic expression of NGB inhibits cell growth, cell aggregation, and tumorigenicity in tumorigenic schwanomma cells. Down-regulation and infrequent mutation of NGB were detected in human glioma cell lines and primary tumors. The interaction of NGB with merlin impairs the turnover of merlin, yet merlin does not affect the GTPase nor GTP-binding activity of NGB. Finally, the tumor suppressor functions of NGB require merlin and are linked to its ability to suppress cyclin D1 expression. Collectively, these findings indicate that NGB is a tumor suppressor that regulates and requires merlin to suppress cell proliferation.
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Sorensen, C. M., R. J. Hayashi, and C. W. Pierce. "Identification of Igh-C-linked determinants on suppressor T cell hybrids and factors specific for L-glutamic acid60-L-alanine30-L-tyrosine10 (GAT)." Journal of Experimental Medicine 162, no. 3 (September 1, 1985): 1044–59. http://dx.doi.org/10.1084/jem.162.3.1044.
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Hyperimmunization of BALB/c mice with concanavalin A-stimulated blasts from the Ig allotype-congenic strain, C.B20, results in the production of antibodies reactive with T cells in an allotype-restricted manner. Spleen cells from these hyperimmune BALB/c mice were used to generate a panel of hybridomas that secrete monoclonal antibodies, reactive, in an allotype-restricted manner, exclusively with T cells subpopulations, and in particular, reactive with suppressor T cell hybridomas and their secreted soluble factors. Two functional classes of antibodies were identified: those that react with single polypeptide-chain suppressor T cell factors (TsF1) and the suppressor T cell hybridomas that produce such factors, and those that react with two polypeptide-chain suppressor T cell factors (TsF2) and their corresponding suppressor T cell hybridomas. These two classes of antibody were used to isolate molecules from the membranes of the respective suppressor T cell hybrids that are functionally and structurally related to the secreted suppressor T cell factors, suggesting a receptor function for these molecules.
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Bohana-Kashtan, Osnat, Hyam Levitsky, and Curt I. Civin. "Identification of New Alloantigen-Reactive CD8+ Cytotoxic and Suppressor T Cell Subpopulations." Blood 110, no. 11 (November 16, 2007): 3229. http://dx.doi.org/10.1182/blood.v110.11.3229.3229.
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We sought to develop a better understanding of the T cells involved in the human allogeneic immune response, in order to eventually engineer a donor graft with reduced GVHD-mediating potential, without ablating general immune competence. Prior studies reported that all the activated CD4+ T cells responding to a specific antigen challenge reside within the CD4high population expressing high levels of membrane CD4. We identified a new population of activated CD8+ T cells that developed during an in vitro allogeneic immune response, along with the allo-activated CD4high T cell population. Analogous to activated CD4+ T cells, this new T cell population was distinguished by up-regulated CD8 (and CD38) expression (CD8highCD38+). In accordance with Martins et al. (Blood 2004, 104:3429), we found that the depletion of the CD4highCD38+ population resulted in reduced 2o response to the original 2nd party stimulators. In contrast, depletion of the CD8highCD38+ population resulted in an increased 2o response to 2nd party cells, with no change in the response to 3rd party or CMV antigens. Elevated numbers of CD8highCD38+ T cells potently reduced the 1o and 2o responses to 2nd party, but not to 3rd party cells or CMV antigens. The complementary, non-activated CD8normalCD38− T cell population had no inhibitory effect. Importantly, we found that CD8highCD38+ T cells mediated both a specific cytotoxic response (that could be inhibited by the pan-caspase inhibitor, Z-VAD), and a specific suppressive response toward the original 2nd party stimulators (that was not affected by Z-VAD), and within this CD8highCD38+ population, there was a subpopulation of cytotoxic T cells (perforin+LAMP1+CD56+CD11b+CD11c+) and a subpopulation of non-cytotoxic T cells. Furthermore, we found that although CD8highCD38+ T cells differentially expressed CD28, both CD8highCD38+CD28− and CD8highCD38+CD28− T cells mediated a cytotoxic as well as a suppressor T cell response toward the original 2nd party cells (different from the published suppressive function of CD8+CD28− T cells observed by Liu et al, Int Immunol 1998, 10:775). Upon separation of cytotoxic CD8highCD38+ T cells from suppressor CD8highCD38+ T cells, we will explore the GVHD potential of these 2 novel activated CD8high T cell subpopulations, in a sensitive in vivo xenograft model for GVHD using NOD/SCID/IL2Rγnull immunodeficient mice.
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Goulart, Michelle R., G. Elizabeth Pluhar, and John R. Ohlfest. "Identification of Myeloid Derived Suppressor Cells in Dogs with Naturally Occurring Cancer." PLoS ONE 7, no. 3 (March 13, 2012): e33274. http://dx.doi.org/10.1371/journal.pone.0033274.
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Vincent, Carr D., Benjamin A. Buscher, Jonathan R. Friedman, Lee Anne Williams, Patrick Bardill, and Joseph P. Vogel. "Identification of Non-dot/icm Suppressors of the Legionella pneumophila ΔdotL Lethality Phenotype." Journal of Bacteriology 188, no. 23 (September 22, 2006): 8231–43. http://dx.doi.org/10.1128/jb.00937-06.
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ABSTRACT Legionella pneumophila, a causative agent of bacterial pneumonia, survives inside phagocytic cells by avoiding rapid targeting to the lysosome. This bacterium utilizes a type IVB secretion system, encoded by the dot/icm genes, to replicate inside host cells. DotL, a critical component of the Dot/Icm secretion apparatus, functions as the type IV coupling protein. In contrast to most dot/icm genes, which are dispensable for growth on bacteriological media, dotL is required for the viability of wild-type L. pneumophila. Previously we reported that ΔdotL lethality could be suppressed by inactivation of the Dot/Icm complex via mutations in other dot/icm genes. Here we report the isolation of non-dot/icm suppressors of this phenotype. These ΔdotL suppressors include insertions that disrupt the function of the L. pneumophila homologs of cpxR, djlA, lysS, and two novel open reading frames, lpg0742 and lpg1594, that we have named ldsA and ldsB for lethality of ΔdotL suppressor. In addition to suppressing ΔdotL lethality, inactivation of these genes in a wild-type strain background causes a range of defects in L. pneumophila virulence traits, including intracellular growth, implicating these factors in the proper function of the Dot/Icm complex. Consistent with previous data showing a role for the cpx system in regulating expression of several dot/icm genes, the cpxR insertion mutant produced decreased levels of three Dot/Icm proteins, DotA, IcmV, and IcmW. The remaining four suppressors did not affect the steady-state levels of any Dot/Icm protein and are likely to represent the first identified factors necessary for assembly and/or activation of the Dot/Icm secretion complex.
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Gabrilovich, Dmitry I. "The Dawn of Myeloid-Derived Suppressor Cells: Identification of Arginase I as the Mechanism of Immune Suppression." Cancer Research 81, no. 15 (August 1, 2021): 3953–55. http://dx.doi.org/10.1158/0008-5472.can-21-1237.
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Choi, Jaebok, Julie Ritchey, and John F. DiPersio. "Generation of Treg-Like Cells from CD4+CD25- T Cells Occurs Via Both Foxp3 Dependent and Independent Pathways." Blood 112, no. 11 (November 16, 2008): 813. http://dx.doi.org/10.1182/blood.v112.11.813.813.
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Abstract Regulatory T cells (Treg) contribute to the maintenance of self-tolerance and have been demonstrated to both suppress autoimmune diseases and mitigate GvHD in mouse models. Major obstacles for their routine use in human clinical trials to reduce autoimmunity or GvHD include the low number of Treg found in the peripheral blood in the resting state (5–10% of CD4+ T cells), low yields and efficiencies of purification and severe limitations maintaining suppressor function after ex vivo expansion. The master gene responsible for the normal development and suppressor function of Treg is Foxp3 which is exclusively expressed in Treg. Recent identification of demethylated CpG islands within the Foxp3 locus only in Treg lead us to investigate whether an FDA-approved demethylating agent, decitabine, could be used to enhance expression of Foxp3 via an epigenetic effect and functionally convert CD4+CD25- T cells into Treg. Treatment of human CD4+CD25-FOXP3- T cells with decitabine in the presence of anti-CD3/CD28 beads and hIL-2 (50u/ml) induced FOXP3 expression. Optimal expression of FOXP3 was seen in those cells incubated with 1–5 uM decitabine. Real time RT-PCR demonstrated levels of mRNA for FOXP3 that were comparable to that seen in bead-activated natural Treg (10–12 fold increase above baseline). This resulted in increased expression at the protein level in 60% of decitabine-treated cells (dcT) (5% of PBS-treated cells (pbsT)). Decitabine also induced Foxp3 expression in 80% of anti-CD3/CD28 bead-activated murine CD4+CD25- T cells. To determine the duration of Foxp3 expression in dcT, we performed intracellular staining for Foxp3 each day for seven days and found that about 50% of dcT were Foxp3+ at day 7. Consistent with these results, decitabine also induced marked increase GFP expression (from undetectable levels) in anti-CD3/CD28 bead-activated CD4+CD25- T cells from Foxp3-ires-GFP KI mice (kindly provided by Tim Ley). In order to identify regulatory elements which mediate decitabine induced expression of Foxp3, we cloned both the 6kb 5′ promoter and the 6kb intron 1 of the human FOXP3 locus upstream of luciferase and tested expression of luciferase in stable Jurkat transfectants +/− decitabine by BLI. Decitabine induced 5–7 fold increase luciferase only in those 5′ transfectants. Of note is that dcT could potently suppress proliferation of CD4+CD25- T cells in vitro (ratio 1:1) in response to both anti-CD3/CD28 bead activation and to allo-APC in mixed lymphocyte cultures. Transwell experiments demonstrated that the suppressor function of dcT is cell-contact dependent. Surprisingly, we found that their suppressive properties are independent of Foxp3 expression in that dcT from Foxp3 KO mice were equally suppressive in bead-based proliferation assays as WT dcT. These data strongly suggest that decitabine may allow for the reexpression of genes such as Foxp3 and critical genes downstream of Foxp3 which mediate the suppressor phenotype in vitro. In murine T-cell depleted BMT model (B6→Balb/c), conventional T-cells (Tconv) (10×106) incubated with anti-CD3/CD28 beads and decitabine were found to promote enhanced engraftment with reduced GvHD, compared to mice receiving PBS-treated Tconv. In addition, addition of dcT with Tconv (1:1 ratio) resulted in decreased GvHD and improved survival, compared to Balb/c recipients receiving B6 Tconv and pbsT. In summary, decitabine-treatment enhanced Foxp3 expression in CD4+CD25- non-Treg cells. These dcT efficiently suppressed the proliferation of allo-reactive T cells in vitro and mitigated GvHD in vivo. The suppressor function of dcT was cell-contact dependent but unexpectedly Foxp3-independent.
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Kaufmann, J., G. Pronk, K. Giese, and A. Klippel. "Identification of novel effectors of invasive cell growth downstream of phosphoinositide 3-kinase." Biochemical Society Transactions 32, no. 2 (April 1, 2004): 355–59. http://dx.doi.org/10.1042/bst0320355.
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Conventional approaches to identifying cancer targets are complicated by the chromosomal instability of tumour cells, and typically result in a large number of differentially expressed candidate genes with uncertain disease relevance. Here we present a novel approach which aims to elucidate the molecular changes that are induced after loss of tumour suppressor function. Using gene silencing tools, we mimic the loss of tumour suppressor function to identify key regulators of tumour initiation and progression. Loss of function of the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) correlates with increased invasive cell growth due to the resulting chronic activation of the PI 3-kinase (phosphoinositide 3-kinase) pathway. Induced activation of PI 3-kinase either by inhibiting PTEN expression or by using p110*, a constitutively active PI 3-kinase, increased signalling and the invasive growth potential of cells. Using this unbiased approach we have identified novel downstream effectors of PI 3-kinase/PTEN signalling that mediate the behaviour of cells with a hyperactive PI 3-kinase pathway. These molecules represent candidate targets for therapeutic intervention in patients with PTEN-deficient tumours.
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Perez, Cristina, Cirino Botta, Aintzane Zabaleta, Noemi Puig, Maria-Teresa Cedena, Ibai Goicoechea, Daniel Alameda, et al. "Immunogenomic identification and characterization of granulocytic myeloid-derived suppressor cells in multiple myeloma." Blood 136, no. 2 (July 9, 2020): 199–209. http://dx.doi.org/10.1182/blood.2019004537.
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Abstract Granulocytic myeloid-derived suppressor cells (G-MDSCs) promote tumor growth and immunosuppression in multiple myeloma (MM). However, their phenotype is not well established for accurate monitoring or clinical translation. We aimed to provide the phenotypic profile of G-MDSCs based on their prognostic significance in MM, immunosuppressive potential, and molecular program. The preestablished phenotype of G-MDSCs was evaluated in bone marrow samples from controls and MM patients using multidimensional flow cytometry; surprisingly, we found that CD11b+CD14−CD15+CD33+HLADR− cells overlapped with common eosinophils and neutrophils, which were not expanded in MM patients. Therefore, we relied on automated clustering to unbiasedly identify all granulocytic subsets in the tumor microenvironment: basophils, eosinophils, and immature, intermediate, and mature neutrophils. In a series of 267 newly diagnosed MM patients (GEM2012MENOS65 trial), only the frequency of mature neutrophils at diagnosis was significantly associated with patient outcome, and a high mature neutrophil/T-cell ratio resulted in inferior progression-free survival (P < .001). Upon fluorescence-activated cell sorting of each neutrophil subset, T-cell proliferation decreased in the presence of mature neutrophils (0.5-fold; P = .016), and the cytotoxic potential of T cells engaged by a BCMA×CD3-bispecific antibody increased notably with the depletion of mature neutrophils (fourfold; P = .0007). Most interestingly, RNA sequencing of the 3 subsets revealed that G-MDSC–related genes were specifically upregulated in mature neutrophils from MM patients vs controls because of differential chromatin accessibility. Taken together, our results establish a correlation between the clinical significance, immunosuppressive potential, and transcriptional network of well-defined neutrophil subsets, providing for the first time a set of optimal markers (CD11b/CD13/CD16) for accurate monitoring of G-MDSCs in MM.
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Schröder, Matthias, Simone Loos, Svenja Kerstin Naumann, Christopher Bachran, Marit Krötschel, Viktor Umansky, Laura Helming, and Lee Kim Swee. "Identification of inhibitors of myeloid-derived suppressor cells activity through phenotypic chemical screening." OncoImmunology 6, no. 1 (November 29, 2016): e1258503. http://dx.doi.org/10.1080/2162402x.2016.1258503.
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Yang, Bingfen, Xinjing Wang, Jing Jiang, Fei Zhai, and Xiaoxing Cheng. "Identification of CD244-expressing myeloid-derived suppressor cells in patients with active tuberculosis." Immunology Letters 158, no. 1-2 (March 2014): 66–72. http://dx.doi.org/10.1016/j.imlet.2013.12.003.
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Stanley, Robert F., Richard T. Piszczatowski, Boris Bartholdy, Kelly Mitchell, Wendy M. McKimpson, Swathi Narayanagari, Dagmar Walter, et al. "A myeloid tumor suppressor role for NOL3." Journal of Experimental Medicine 214, no. 3 (February 23, 2017): 753–71. http://dx.doi.org/10.1084/jem.20162089.
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Despite the identification of several oncogenic driver mutations leading to constitutive JAK–STAT activation, the cellular and molecular biology of myeloproliferative neoplasms (MPN) remains incompletely understood. Recent discoveries have identified underlying disease-modifying molecular aberrations contributing to disease initiation and progression. Here, we report that deletion of Nol3 (Nucleolar protein 3) in mice leads to an MPN resembling primary myelofibrosis (PMF). Nol3−/− MPN mice harbor an expanded Thy1+LSK stem cell population exhibiting increased cell cycling and a myelomonocytic differentiation bias. Molecularly, this phenotype is mediated by Nol3−/−-induced JAK–STAT activation and downstream activation of cyclin-dependent kinase 6 (Cdk6) and Myc. Nol3−/− MPN Thy1+LSK cells share significant molecular similarities with primary CD34+ cells from PMF patients. NOL3 levels are decreased in CD34+ cells from PMF patients, and the NOL3 locus is deleted in a subset of patients with myeloid malignancies. Our results reveal a novel genetic PMF-like mouse model and identify a tumor suppressor role for NOL3 in the pathogenesis of myeloid malignancies.
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Gueller, Saskia, Martina Komor, Julian C. Desmond, Oliver G. Ottmann, Dieter Hoelzer, H. Phillip Koeffler, and Wolf-Karsten Hofmann. "Identification of Putative New Tumor Suppressor Genes in Highly Purified CD34+ Bone Marrow Cells from Patients with Myelodysplastic Syndromes." Blood 104, no. 11 (November 16, 2004): 204. http://dx.doi.org/10.1182/blood.v104.11.204.204.
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Abstract Activation of transcription of DNA by demethylation and hyperacetylation is known to cause hematologic improvement in patients with myelodysplastic syndromes (MDS). In this study we discriminated genes not expressed in CD34+ cells from untreated patients with MDS but activated by in vitro demethylation (2-aza-5-deoxycytidine, Decitabine) and hyperacetylation (suberoylanilide hydroxamic acid, SAHA). Highly purified CD34+ cells from normal individuals (n=3) and patients with low (n=3) and high (n=3) risk MDS were cultured with SCF (50 ng/ml), IL-3 (10 ng/ml) and GM-CSF (10 ng/ml). The cells were treated with 5 μmol Decitabine on day 1 and supplemented with 2.5 μmol SAHA on day 4 of culture. On day 5, global gene expression in these cells was compared to untreated cells (HG-U133A, Affymetrix, Santa Clara, CA). We identified 50 genes which are not expressed in untreated MDS CD34+ cells but 3-fold induced in all MDS samples by Decitabine and SAHA. Thirty-one of these genes were found to be expressed in normal CD34+ cells underlining the importance of such genes for normal hematopoiesis. This set of genes includes two genes for growth arrest and DNA damage control, the inducible protein beta (GADD45B), a regulator of growth and apoptosis and neural cell adhesion molecule 1 (NCAM1) that plays an important role in cell migration. Furthermore, hematological and neurological expressed 1 (HN1) which was not expressed in MDS CD34+ cells is known to have an anti-proliferative effect on tumor cell lines. N-myc downstream regulated 3 (NDRG3) is up-regulated during normal cell differentiation and suppressed in several tumor cells. In normal CD34+ cells, after in vitro treatment with Decitabine and SAHA we have discriminated 52 genes to be 3-fold up-regulated compared to untreated cells. Thirty-eight of these genes (73 %) were not inducible by demethylation and hyperacetylation in MDS CD34+ cells. These genes include chemokine receptor 3 (CCR3), a receptor for a C-C type chemokine involved in signal transduction, integrin beta-7 (ITGB7) that plays a role in adhesive interactions of leukocytes, preferentially expressed antigen in melanoma (PRAME) which is frequently expressed in human solid cancers and acute leukemia and tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) that recruits apoptotic suppressors and mediates most of the metabolic effects of TNF-alpha. The silencing of these genes is independent of methylation and acetylation state and might be due to other mechanisms. This study shows that in CD34+ cells from MDS patients several genes are suppressed by methylation and hypoacetylation but can be activated by treatment with Decitabine and SAHA. Some of these genes are present in normal untreated CD34+ cells which leads to the assumption that they might function as tumor suppressor genes. Low or absent expression of these genes may contribute to the clonal expansion of MDS CD34+ which can be overcome by treatment with Decitabine or SAHA. Furthermore, the knowledge about these target genes may enable a more specific evaluation of the mechanisms of action of demethylating/hyperacetylating agents.
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Khan, Shaheena, Jennifer L. Taylor, and Carrie W. Rinker-Schaeffer. "Disrupting Ovarian Cancer Metastatic Colonization: Insights from Metastasis Suppressor Studies." Journal of Oncology 2010 (2010): 1–7. http://dx.doi.org/10.1155/2010/286925.
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Ovarian cancer affects approximately 25,000 women in the United States each year and remains one of the most lethal female malignancies. A standard approach to therapy is surgical cytoreduction, after which the remaining microscopic residual disease is treated with chemotherapy. The vast majority of patients have disease recurrence, underscoring the crucial need for approaches to control the regrowth, or colonization, of tissues after local treatment. Improved therapies require mechanistic information about the process of metastatic colonization, the final step in metastasis, in which cancer cells undergo progressive growth at secondary sites. Studies of metastasis suppressors are providing insights into events controlling metastatic colonization. This paper reviews our laboratory's approach to the identification, characterization, and functional testing of the JNKK1/MKK4 metastasis suppressor in ovarian cancer metastatic colonization. Specifically, we demonstrate that interaction of ovarian caner cells with the omental microenvironment activates JNKK1/MKK4 resulting in decreased proliferation without affecting apoptosis. The potential role of the omental microenvironment, specifically milky spot structures, is also described. It is our goal to provide this work as a usable paradigm that will enable others to study metastasis suppressors in clinical and experimental ovarian cancer metastases.
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Kennah, Erin, Ashley Ringrose, Liang L. Zhou, Sharmin Esmailzadeh, Hong Qian, Ming-wan Su, Youwen Zhou, and Xiaoyan Jiang. "Identification of tyrosine kinase, HCK, and tumor suppressor, BIN1, as potential mediators of AHI-1 oncogene in primary and transformed CTCL cells." Blood 113, no. 19 (May 7, 2009): 4646–55. http://dx.doi.org/10.1182/blood-2008-08-174037.
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Abstract AHI-1 is an oncogene often targeted by provirus insertional mutagenesis in murine leukemias and lymphomas. Aberrant expression of human AHI-1 occurs in cutaneous T-cell lymphoma (CTCL) cells and in CD4+CD7− Sezary cells from patients with Sezary syndrome. Stable knockdown of AHI-1 using retroviral-mediated RNA interference in CTCL cells inhibits their transforming activity in vitro and in vivo. To identify genes involved in AHI-1–mediated transformation, microarray analysis was performed to identify differentially expressed genes in AHI-1–suppressed CTCL cells. Fifteen up-regulated and 6 down-regulated genes were identified and confirmed by quantitative reverse transcription-polymerase chain reaction. Seven were further confirmed in a microarray analysis of CD4+CD7− Sezary cells from Sezary syndrome patients. HCK and BIN1 emerged as new candidate cooperative genes, with differential protein expression, which correlates with observed transcript changes. Interestingly, changes in HCK phosphorylation and biologic response to its inhibitor, dasatinib, were observed in AHI-1–suppressed or –overexpressed cells. The tumor suppressor BIN1 physically interacts with MYC in CTCL cells, which also exhibit differential MYC protein expression. In addition, aberrant expression of alternative splicing forms of BIN1 was observed in primary and transformed CTCL cells. These findings indicate that HCK and BIN1 may play critical roles in AHI-1–mediated leukemic transformation of human CTCL cells.
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Hara, Hideo, Yusuke Nanri, Emi Tabata, Saori Mitsutake, and Takeshi Tabira. "Identification of astrocyte-derived immune suppressor factor that induces apoptosis of autoreactive T cells." Journal of Neuroimmunology 233, no. 1-2 (April 2011): 135–46. http://dx.doi.org/10.1016/j.jneuroim.2010.12.011.
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Castellano, L., J. Waxman, G. Giamas, C. Apostolopous, and J. Stebbing. "The identification of new tumour suppressor micrornas epigenetically silenced in drug resistant cancer cells." European Journal of Cancer Supplements 6, no. 9 (July 2008): 95. http://dx.doi.org/10.1016/s1359-6349(08)71541-6.
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Sherger, Matthew, William Kisseberth, Cheryl London, Susan Olivo-Marston, and Tracey L. Papenfuss. "Identification of myeloid derived suppressor cells in the peripheral blood of tumor bearing dogs." BMC Veterinary Research 8, no. 1 (2012): 209. http://dx.doi.org/10.1186/1746-6148-8-209.
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Rivera, Claudio Alberto, George A. Dominguez, Vesselin Tomov, Gary W. Falk, Gregory G. Ginsberg, Dmitry Gabrilovich, Anil K. Rustgi, and John P. Lynch. "Identification of Myeloid Derived Suppressor Cells in the Barrett’s Metaplasia to Esophageal Adenocarcinoma Sequence." Gastroenterology 152, no. 5 (April 2017): S234. http://dx.doi.org/10.1016/s0016-5085(17)31071-5.
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Wang, Ying, Peng Li, Bo Wang, Shuai Wang, and Pinan Liu. "Identification of myeloid-derived suppressor cells that have an immunosuppressive function in NF2 patients." Journal of Cancer Research and Clinical Oncology 145, no. 2 (January 2, 2019): 523–33. http://dx.doi.org/10.1007/s00432-018-02825-8.
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Schmidt, Eva, Jana Krosl, Jalila Chagraoui, Nadine Mayotte, Caroline Pabst, Tara McRae, and Guy Sauvageau. "Identification of Lats 1 As a Putative Tumor Suppressor in HoxA9/Meis Induced Leukemia." Blood 118, no. 21 (November 18, 2011): 2474. http://dx.doi.org/10.1182/blood.v118.21.2474.2474.
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Abstract Abstract 2474 Aberrant expression of Hox genes and their cofactors Pbx and Meis1 has been detected in approximately 50% of all human leukemias, and proteins interacting with these homeodomain factors could play a major role in leukemia development. Studies in drosophila showed that hth/MEIS directly interacts with YKI, a component of the Hippo signaling pathway (Peng HW et al., 2009). The core components of this pathway in the mammalian cells are the kinases MST 1 or 2 and LATS 1 or 2, and the downstream transcription cofactors WWTR1 and YAP (homologues of the drosophila Yki). The Hippo pathway has been proposed to play a tumor suppressive role in carcinoma development (Lu L et al. 2010), but little is known about its function in hematopoiesis and leukemia. To address this issue, we first determined the expression levels of the core Hippo pathway constituents in different subpopulations of primitive hematopoietic cells by quantitative RT-PCR. Hematopoietic stem cells (HSC) isolated from day 14.5 fetal liver (FL-HSC, phenotype: CD150+CD48-Lin-), or bone marrow from 3 and 4 week old mice (BM-HSC, phenotype: cKit+CD150+CD48-Lin-) express comparable levels of Lats 1/2 and Mst 1/2. FL-HSC, however, express approximately 3 fold higher levels of Wwtr1 and Yap than the BM-HSC. Expression of all core components of the Hippo pathway was also detected in the Hoxa9+Meis1-induced leukemia named FLA2 in which approximately 70% of cells represent leukemia stem cells (LSC). The role of this pathway in leukemia was assessed using the shRNA-mediated loss of function approach. For each core component, 5 different shRNAs were designed, and 2 achieving ≥40% decrease in the targeted transcript levels were selected for the in vivo experiments. Freshly isolated FLA2 leukemia cells were infected with recombinant retroviruses carrying the control shLuciferase or the targeting shRNA, and green fluorescent protein (GFP), and were transplanted into sub-lethally irradiated recipient mice. The proportions of shRNA transduced (GFP+) cells were determined at the time of transplantation (day 0), and at the time of sacrifice (day 18 ± 2). During this period, the proportions of shWwtr1(GFP+) cells to the leukemic cell populations decreased to 10–20% of the initial day 0 values. Conversely, the Lats1 knockdown leads to > 50% increase over the initial proportion of the GFP+ cells. The combined Lats1+Lats2 knockdown enhanced the competitiveness of the transduced cells compared shLuciferase controls. These significant results (p < 0.05, Mann-Whitney-Test) suggest that LATS kinases act as negative regulators of leukemic cell expansion. To exclude the possibility that this effect is limited to FLA2 leukemia we isolated the CD150+CD48-Lin- stem/progenitor cells from FL, co-infected them first with Hoxa9 and Meis1 cDNA carrying retroviruses, and then knocked down Wwtr1 or Lats1. Similar to observations in FLA2 leukemia model, Lats 1 depletion promoted ∼2-fold increase, and Wwtr 1 reduction >80% decrease in proportions of the transduced (GFP+) cells compared to their initial day 0 levels. Together, our observations suggest that LATS kinases act as negative modulators of Hox/Meis-induced leukemia and indicate a possibility for a specific targeting of the Hox/Meis-activated cellular pathways. Disclosures: No relevant conflicts of interest to declare.
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Asou, Hiroya, Yuko Ozaki, Akiko Nagamachi, Daisuke Aki, Hirotaka Matsui, and Toshiya Inaba. "Identification of Two 7q Genes Encoding Centrosomal Proteins as Myeloid Tumor-Suppressor Candidates." Blood 112, no. 11 (November 16, 2008): 1793. http://dx.doi.org/10.1182/blood.v112.11.1793.1793.
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Abstract We previously reported a candidate myeloid tumor-suppressor gene Miki (mitotic kinetic regulator, LOC253012) isolated from a common microdeletion cluster in chromosome subband 7q21.2 that was identified by microarray-based CGH analyses of JMML (ASH Annual Meeting, 2006 and 2007). Deletion of one Miki gene was also detected in 28 % of adult MDS/AML patients by copy-number assessment using real-time quantitative PCR (qPCR). Miki encodes a centrosomal protein: downregulation of Miki by siRNA disturbs the maturation and positioning of centrosomes, as well as spindle formation in mitotic cells, resulting in severe mitotic defects, such as chromosome lagging and proanaphase arrest. This causes abnormal nuclear morphology. When Miki expression levels were constitutively reduced by short-hairpin (sh) RNA in K562 cells, morphology of cells changed drastically: bi- tri- or multiple-nuclear cells with or without micronuclei appeared frequently that strikingly resembled the bone marrow picture of MDS. In addition, FISH analysis revealed widely varying chromosome numbers in these cells, suggesting that Miki-downregulation induces chromosome instability. Six myeloid leukemia cell lines derived from MDS/AML patients with monosomy 7 generally expressed Miki protein at very low (but detectable) levels, suggesting that haploinsufficient effects and/or epigenetic mechanisms reduce Miki expression levels. These six lines harboring monosomy 7 showed severe abnormal mitosis and nuclear morphology, and induction of Miki to these cells using a retroviral vector restored normal mitosis. These findings suggested that loss of Miki gene contributes to myelodysplasia and chromosome instability, which are characteristic of -7/7q- MDS/AML. To elucidate molecular mechanism through which Miki plays roles in centrosomal maturation and spindle formation, we tried to identify proteins associated with Miki using yeast two hybrid assay or mass spectrometry and found that a centrosomal giant scaffold protein CG-NAP (also known as AKAP9/AKAP450/yotiao) binds to Miki in a G2/M specific manner. Intriguingly, CG-NAP gene locates to subband 7q21.2, 1.2 Mb centromeric to Miki gene. qPCR revealed that CG-NAP was also frequently deleted in adult MDS/AML (36 %) and protein expression levels were very low (but detectable) in six cell lines derived from MDS/AML with monosomy 7, raising a possibility that CG-NAP is another candidate for the responsible genes of 7q deletion. CG-NAP is known to promote microtubule nucleation in centrosomes. As expected, downregulation of CG-NAP by siRNA showed abnormal spindle formation and mitotic disturbance (proanaphase arrest and chromosome lagging) similar to those by Miki-downregulation. Moreover, constitutive downregulation of CG-NAP by shRNA transformed K562 cells to bi- tri- or multiple-nuclear with or without micronuclei, indicating that the Miki/CG-NAP protein complex is responsible for the mitotic disturbance and abnormal nuclear morphology. Finally, we found that CG-NAP does not localize to mitotic centrosomes when Miki expression is downregulated by siRNA, suggesting that Miki contributes to organized progression of mitosis by transporting and/or anchoring CG-NAP to mitotic centrosomes. Our data indicate that Miki and CG-NAP in subband 7q21.2 encode centrosomal proteins, which play critical roles in mitosis. Loss of one 7q allele would cause marked reduction of these two gene products, resulting in myelodysplasia and chromosome instability.
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Dieckmann, Detlef, Heidi Plottner, Susanne Berchtold, Thomas Berger, and Gerold Schuler. "Ex Vivo Isolation and Characterization of Cd4+Cd25+ T Cells with Regulatory Properties from Human Blood." Journal of Experimental Medicine 193, no. 11 (June 4, 2001): 1303–10. http://dx.doi.org/10.1084/jem.193.11.1303.
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It has been known for years that rodents harbor a unique population of CD4+CD25+ “professional” regulatory/suppressor T cells that is crucial for the prevention of spontaneous autoimmune diseases. Here we demonstrate that CD4+CD25+CD45RO+ T cells (mean 6% of CD4+ T cells) are present in the blood of adult healthy volunteers. In contrast to previous reports, these CD4+CD25+ T cells do not constitute conventional memory cells but rather regulatory cells exhibiting properties identical to their rodent counterparts. Cytotoxic T lymphocyte–associated antigen (CTLA)-4 (CD152), for example, which is essential for the in vivo suppressive activity of CD4+CD25+ T cells, was constitutively expressed, and remained strongly upregulated after stimulation. The cells were nonproliferative to stimulation via their T cell receptor for antigen, but the anergic state was partially reversed by interleukin (IL)-2 and IL-15. Upon stimulation with allogeneic (but not syngeneic) mature dendritic cells or platebound anti-CD3 plus anti-CD28 the CD4+CD25+ T cells released IL-10, and in coculture experiments suppressed the activation and proliferation of CD4+ and CD8+ T cells. Suppression proved IL-10 independent, yet contact dependent as in the mouse. The identification of regulatory CD4+CD25+ T cells has important implications for the study of tolerance in man, notably in the context of autoimmunity, transplantation, and cancer.
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Middleton, Melissa Kristine, Alicia Marie Zukas, Tanya Rubinstein, Michele Jacob, Peijuan Zhu, Liang Zhao, Ian Blair, and Ellen Puré. "Identification of 12/15-lipoxygenase as a suppressor of myeloproliferative disease." Journal of Experimental Medicine 203, no. 11 (October 16, 2006): 2529–40. http://dx.doi.org/10.1084/jem.20061444.
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Though Abl inhibitors are often successful therapies for the initial stages of chronic myelogenous leukemia (CML), refractory cases highlight the need for novel molecular insights. We demonstrate that mice deficient in the enzyme 12/15-lipoxygenase (12/15-LO) develop a myeloproliferative disorder (MPD) that progresses to transplantable leukemia. Although not associated with dysregulation of Abl, cells isolated from chronic stage 12/15-LO–deficient (Alox15) mice exhibit increased activation of the phosphatidylinositol 3–kinase (PI3-K) pathway, as indicated by enhanced phosphorylation of Akt. Furthermore, the transcription factor interferon consensus sequence binding protein (ICSBP) is hyperphosphorylated and displays decreased nuclear accumulation, translating into increased levels of expression of the oncoprotein Bcl-2. The ICSBP defect, exaggerated levels of Bcl-2, and prolonged leukemic cell survival associated with chronic stage Alox15 MPD are all reversible upon treatment with a PI3-K inhibitor. Remarkably, the evolution of Alox15 MPD to leukemia is associated with additional regulation of ICSBP on an RNA level, highlighting the potential usefulness of the Alox15 model for understanding the transition of CML to crisis. Finally, 12/15-LO expression suppresses the growth of a human CML–derived cell line. These data identify 12/15-LO as an important suppressor of MPD via its role as a critical upstream effector in the regulation of PI3-K–dependent ICSBP phosphorylation.
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Shen, John P., Rohith Srivas, Ana Bojorquez-Gomez, Katherine Licon, Jian Feng Li, Robert W. Sobol, and Trey Ideker. "Cross-species synthetic lethal interaction screening as a strategy for the identification of novel therapeutic targets in cancer." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 11105. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.11105.
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11105 Background: Mutation, deletion, or epigenetic silencing of tumor suppressor genes is a near universal feature of malignant cells. However, therapeutic strategies for restoring the function of mutated or deleted genes have proven difficult. Synthetic lethality, an event in which the simultaneous perturbation of two genes results in cellular death, has been proposed as a method to selectively target cancer cells. Identifying and pharmacologically inhibiting proteins encoded by genes that are synthetic lethal with known tumor suppressor mutations should result in selective toxicity to tumor cells. Methods: To identify candidate target proteins we measured all pair-wise genetic interactions between all known orthologs of human tumor suppressor genes (162 genes) and all orthologs of druggable human proteins (~400 genes) in the model organism S. Cerevisiae. Analysis of the data uncovered 2,087 distinct synthetic lethal interactions between a tumor suppressor and druggable gene. A computational algorithm was then developed to identify those interactions which were likely to be conserved in humans based on conservation of the synthetic lethal relationship in the distant fission yeast S. pombe. Results: Our bioinformatic analysis suggested a high probability of conservation of the synthetic lethal interactions between the yeast RAD51 (ortholog of BRCA1) and RAD57 (ortholog of XRCC3) with HDA1 (a histone deacetylase; HDAC). We confirmed this by treating LN428 cells with stable lentiviral knockdown of BRCA1 or XRCC3 with the HDAC inhibitors vorinostat (SAHA) and entinostat (MS-275). Both the BRCA1 and XRCC3 knockdown cell lines were significantly more sensitive to HDAC inhibition relative to wild-type (non-silencing lentiviral control) cell line (Table). Conclusions: These results demonstrate that high-throughput approaches for screening synthetic lethal interactions in model organisms such as S. cerevisiae and S. pombecan serve as a valuable resource in helping to identify novel therapeutic targets in human cancer. [Table: see text]
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Del Priore, V., C. A. Snay, A. Bahr, and C. N. Cole. "The product of the Saccharomyces cerevisiae RSS1 gene, identified as a high-copy suppressor of the rat7-1 temperature-sensitive allele of the RAT7/NUP159 nucleoporin, is required for efficient mRNA export." Molecular Biology of the Cell 7, no. 10 (October 1996): 1601–21. http://dx.doi.org/10.1091/mbc.7.10.1601.
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RAT7/NUP159 was identified previously in a screen for genes whose products are important for nucleocytoplasmic export of poly(A)+ RNA and encodes an essential nucleoporin. We report here the identification of RSS1 (Rat Seven Suppressor) as a high-copy extragenic suppressor of the rat7-1 temperature-sensitive allele. Rss1p encodes a novel essential protein of 538 amino acids, which contains an extended predicted coiled-coil domain and is located both at nuclear pore complexes (NPCs) and in the cytoplasm. RSS1 is the first reported high-copy extragenic suppressor of a mutant nucleoporin. Overexpression of Rss1p partially suppresses the defects in nucleocytoplasmic export of poly(A)+ RNA, rRNA synthesis and processing, and nucleolar morphology seen in rat7-1 cells shifted to the nonpermissive temperature of 37 degrees C and, thus, restores these processes to levels adequate for growth at a rate approximately one-half that of wild-type cells. After a shift to 37 degrees C, the mutant Rat7-1p/Nup159-1p is lost from the nuclear rim of rat7-1 cells and NPCs, which are clustered together in these cells grown under permissive conditions become substantially less clustered. Overexpression of Rss1p did not result in retention of the mutant Rat7-1p/Nup159-1p in NPCs, but it did result in partial maintenance of the NPC-clustering phenotype seen in mutant cells. Depletion of Rss1p by placing the RSS1 open reading frame (ORF) under control of the GAL1 promoter led to cessation of growth and nuclear accumulation of poly(A)+ RNA without affecting nuclear protein import or nuclear pore complex distribution, suggesting that RSS1 is directly involved in mRNA export. Because both rat7-1 cells and cells depleted for Rss1p are defective in mRNA export, our data are consistent with both gene products playing essential roles in the process of mRNA export and suggest that Rss1p overexpression suppresses the growth defect of rat7-1 cells at 37 degrees C by acting to maintain mRNA export.
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Rosin, Flávia Cristina Perillo, Juliana Figueredo Pedregosa, Joaquim Soares de Almeida, and Valquiria Bueno. "Identification of myeloid-derived suppressor cells and T regulatory cells in lung microenvironment after Urethane-induced lung tumor." International Immunopharmacology 11, no. 7 (July 2011): 873–78. http://dx.doi.org/10.1016/j.intimp.2010.12.025.
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Desmond, J. C., S. D. Raynaud, L. C. Jones, W. K. Hofmann, T. Haferlach, and H. Phillip Koeffler. "Identification of Epigenetically Silenced Tumor Suppressor Genes in Myeloid Disorders Leads to the Identification of α-Catenin as a Target Gene in 5q- Syndrome." Blood 104, no. 11 (November 16, 2004): 2565. http://dx.doi.org/10.1182/blood.v104.11.2565.2565.
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Abstract CpG islands in the 5′ regulatory regions of genes are generally protected from cytosine methylation as methylation in a promoter can result in transcriptional silencing of the associated gene. Failure of a cell to prevent methylation in the promoter regions of tumor suppressor genes contributes to the onset and progression of cancers. The demethylating agent 5-aza-2′deoxycytidine (DAC) and the histone deacetylase inhibitor suberoyl anilide bishydroxamide (SAHA) possess potent antitumorigenic properties against myeloid disorders. Understanding the alterations of the transcriptome mediated by these drugs should prove vital in uncovering potential tumor suppressor genes epigenetically silenced in myeloid disorders. To this end, we used DAC and SAHA to induce expression of methylated genes in the CD34+ AML cell line KG-1. Expression levels of over 22,000 genes were compared between normal CD34+ cells and treated and untreated KG-1 cells using Affymetrix HG-U133A GeneChip® micoarrays. Statistical analyses revealed 76 genes constitutively expressed in normal CD34+ stem cells, absent in KG-1 cells but whose expression was induced in KG-1 after drug treatment. 39 (51%) of these genes harbored a CpG island in their 5′ regulatory regions, representing potentially methylated tumor suppressor genes in AML. To fit the tumor suppressor paradigm, we hypothesized that any gene possessing antitumorigenic properties would not be expressed in a number of AML patient samples. We examined the expression level of our 39 genes in 120 AML patient samples using microarray analyses. 20 patients belonging to each of the following AML karyotypic groups were analyzed: t(8;21), t(15:17), inv(16), 11q23/MLL, complex and normal karyotpye. Of special note were 8 genes, whose expression was markedly diminished in a subset of patients across all AML karyotypes examined: DAR22, TFIIS, EH-3, ENO2, MXA, DRAL, ASTML and MG50. These represent strong candidates for tumor suppressor genes in AML. Unsupervised clustering analyses using our original 39 genes were performed upon microarray data obtained from patients with myeloproliferative disease (MPD). A subset of 10 genes discriminated between granulocyte samples obtained from healthy donors and those obtained from a subset of agnogenic myeloid metaplasia, essential thronbocythemia and polycythemia vera patients. One of these genes, α-catenin, is located at q31 of chromosome 5, a hot spot for deletion in MDS and AML. α-catenin was expressed in all 120 primary AML samples, including those harboring deletions in chromosome 5. However, Real Time PCR analysis of 32 MDS patients harboring a 5q deletion in the region of α-catenin showed a marked decrease in expression of this gene compared to 20 non 5q- MDS patients. Neighboring genes in the deleted region of 5q did not show as marked a decrease in expression, suggesting loss of expression of both α-catenin alleles in these patients. These findings imply a double hit mechanism in 5q- MDS, where loss of one allele of α-catenin through deletion is supplemented by epigenetic silencing (directly or indirectly) of the second allele. In summary, we have uncovered groups of genes that may be involved in the pathogenesis of AML and various MPDs by virtue of their transcriptional repression through epigenetic events. Importantly, we have identified α-catenin as a key gene on chromosome 5, whose expression is lost in 5q- MDS.
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Horrigan, Stephen K., Zarema H. Arbieva, Hong Yan Xie, Jelena Kravarusic, Noreen C. Fulton, Haley Naik, Tiffany T. Le, and Carol A. Westbrook. "Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31." Blood 95, no. 7 (April 1, 2000): 2372–77. http://dx.doi.org/10.1182/blood.v95.7.2372.
Full textAbstract:
Abstract Interstitial deletion or loss of chromosome 5 is frequent in malignant myeloid disorders, including myelodysplasia (MDS) and acute myeloid leukemia (AML), suggesting the presence of a tumor suppressor gene. Loss of heterozygosity (LOH) analysis was used to define a minimal deletion interval for this gene. Polymorphic markers on 5q31 were identified using a high-resolution physical and radiation hybrid breakpoint map and applied to a patient with AML with a subcytogenetic deletion of 5q. By comparing the DNA from leukemic cells to buccal mucosa cells, LOH was detected with markers D5S476 and D5S1372 with retention of flanking markers D5S500 to D5S594. The D5S500–D5S594 interval, which covers approximately 700 kb, thus represents a minimal localization for the tumor suppressor gene. Further refinement of the physical map enabled the specification of 9 transcription units within the encompassing radiation hybrid bins and 7 in flanking bins. The 9 candidates include genes CDC25, HSPA9, EGR1, CTNNA1, and 5 unknown ESTs. Reverse-transcription polymerase chain reaction confirms that all of them are expressed in normal human bone marrow CD34+ cells and in AML cell lines and thus represent likely candidates for the MDS–AML tumor suppressor gene at 5q31.
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Horrigan, Stephen K., Zarema H. Arbieva, Hong Yan Xie, Jelena Kravarusic, Noreen C. Fulton, Haley Naik, Tiffany T. Le, and Carol A. Westbrook. "Delineation of a minimal interval and identification of 9 candidates for a tumor suppressor gene in malignant myeloid disorders on 5q31." Blood 95, no. 7 (April 1, 2000): 2372–77. http://dx.doi.org/10.1182/blood.v95.7.2372.007k20_2372_2377.
Full textAbstract:
Interstitial deletion or loss of chromosome 5 is frequent in malignant myeloid disorders, including myelodysplasia (MDS) and acute myeloid leukemia (AML), suggesting the presence of a tumor suppressor gene. Loss of heterozygosity (LOH) analysis was used to define a minimal deletion interval for this gene. Polymorphic markers on 5q31 were identified using a high-resolution physical and radiation hybrid breakpoint map and applied to a patient with AML with a subcytogenetic deletion of 5q. By comparing the DNA from leukemic cells to buccal mucosa cells, LOH was detected with markers D5S476 and D5S1372 with retention of flanking markers D5S500 to D5S594. The D5S500–D5S594 interval, which covers approximately 700 kb, thus represents a minimal localization for the tumor suppressor gene. Further refinement of the physical map enabled the specification of 9 transcription units within the encompassing radiation hybrid bins and 7 in flanking bins. The 9 candidates include genes CDC25, HSPA9, EGR1, CTNNA1, and 5 unknown ESTs. Reverse-transcription polymerase chain reaction confirms that all of them are expressed in normal human bone marrow CD34+ cells and in AML cell lines and thus represent likely candidates for the MDS–AML tumor suppressor gene at 5q31.
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Porta, Giuseppe Della, Paolo Radice, and Marco A. Pierotti. "Onco-Suppressor Genes in Human Cancer." Tumori Journal 75, no. 4 (August 1989): 329–36. http://dx.doi.org/10.1177/030089168907500406.
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The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an oncosuppressor gene are inactivated. The mutations affecting their normal functions belong to the type « loss of function ». The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell. Finally, the increasing availability of DNA markers, defining restriction fragment length polymorphisms, has led to the mapping of the loci of inherited predisposition for familial cancer syndromes such as MEN-1, VHL and NF-2 and to the extension to common cancers of the allele losses analysis that can reveal onco-suppressor gene inactivation. This indirect approach has suggested the occurrence of different onco-suppressor genes for sporadic breast, colonic and lung cancers, bladder carcinoma, germinal tumors of the testis and malignant melanoma. In particular, colonic cancer provides a significant example of a possible multistep scenario for carcinogenesis in humans in which activated oncogenes (e.g. ras) and inactivated putative onco-suppressor genes (on chromosome 17 and 18) coexist in the same cell.
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Liu, Yun, Rihua Zhang, Jing Xin, Yan Sun, Jie Li, Dong Wei, and Allan Z. Zhao. "Identification of S100A16 as a Novel Adipogenesis Promoting Factor in 3T3-L1 Cells." Endocrinology 152, no. 3 (March 1, 2011): 903–11. http://dx.doi.org/10.1210/en.2010-1059.
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S100A16 is a member of S100 protein super family that carries calcium-binding EF-hand motifs. Its expression is ubiquitous and elevated in various types of tumors. The functions of S100 proteins are still being defined, although many members of S100 protein family are traditionally considered as markers of tumor tissues. Using 3T3-L1 preadipocyte model, we investigated the expression and function of S100A16 during differentiation into adipocytes as well as the potential roles of S100A16 in the regulation of insulin sensitivity. We found that the expression of S100A16 was increased during differentiation and that elevation of intracellular Ca2+ via calcium ionophores led to its nucleus exclusion. Overexpression of S100A16 in 3T3-L1 preadipocytes increased their proliferation and markedly enhanced adipogenesis but resulted in significant reduction of insulin-stimulated glucose uptake and phosphorylation of AKT. In contrast, suppression of S100A16 expression with two different types of RNA interference significantly inhibited adipogenesis and preadipocyte proliferation. Immunoprecipitation analysis revealed that S100A16 could physically interact with tumor suppressor protein p53, also a known inhibitor of adipogenesis. Overexpression or RNA interference–initiated reduction of S100A16 led to the inhibition or activation of the expression of p53-responsive genes, respectively. Interestingly, Western blot assays showed that S100A16 protein levels were markedly higher in the adipose tissues of diet-induced obese mice and the ob/ob mice than that in control lean mice. Thus, we reveal for the first time that S100A16 protein is a novel adipogenesis-promoting factor and that increased expression of S100A16 in 3T3-L1 adipocytes can have a negative impact on insulin sensitivity.
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ROWDEN, G., D. DAVIS, D. LUCKETT, and L. POULTER. "Identification of CD4+, 2H4 + (T8γ +) suppressor-inducer cells in normal human epidermis and superficial dermis." British Journal of Dermatology 119, no. 2 (August 1988): 147–54. http://dx.doi.org/10.1111/j.1365-2133.1988.tb03195.x.
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Aichberger, Karl J., Karoline V. Gleixner, Irina Mirkina, Sabine Cerny-Reiterer, Barbara Peter, Veronika Ferenc, Michael Kneidinger, et al. "Identification of proapoptotic Bim as a tumor suppressor in neoplastic mast cells: role of KIT D816V and effects of various targeted drugs." Blood 114, no. 26 (December 17, 2009): 5342–51. http://dx.doi.org/10.1182/blood-2008-08-175190.
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Abstract Systemic mastocytosis (SM) is a myeloid neoplasm involving mast cells (MCs) and their progenitors. In most cases, neoplastic cells display the D816V-mutated variant of KIT. KIT D816V exhibits constitutive tyrosine kinase (TK) activity and has been implicated in increased survival and growth of neoplastic MCs. Recent data suggest that the proapoptotic BH3-only death regulator Bim plays a role as a tumor suppressor in various myeloid neoplasms. We found that KIT D816V suppresses expression of Bim in Ba/F3 cells. The KIT D816–induced down-regulation of Bim was rescued by the KIT-targeting drug PKC412/midostaurin. Both PKC412 and the proteasome-inhibitor bortezomib were found to decrease growth and promote expression of Bim in MC leukemia cell lines HMC-1.1 (D816V negative) and HMC-1.2 (D816V positive). Both drugs were also found to counteract growth of primary neoplastic MCs. Furthermore, midostaurin was found to cooperate with bortezomib and with the BH3-mimetic obatoclax in producing growth inhibition in both HMC-1 subclones. Finally, a Bim-specific siRNA was found to rescue HMC-1 cells from PKC412-induced cell death. Our data show that KIT D816V suppresses expression of proapoptotic Bim in neoplastic MCs. Targeting of Bcl-2 family members by drugs promoting Bim (re)-expression, or by BH3-mimetics such as obatoclax, may be an attractive therapy concept in SM.