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Journal articles on the topic "RUNX"
1
Chuang, Linda Shyue Huey, Jian Ming Khor, Soak Kuan Lai, Shubham Garg, Vaidehi Krishnan, Cheng-Gee Koh, Sang Hyun Lee, and Yoshiaki Ito. "Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression." Proceedings of the National Academy of Sciences 113, no. 23 (May 23, 2016): 6490–95. http://dx.doi.org/10.1073/pnas.1523157113.
Full textAbstract:
The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity.
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Shin, Boyoung, Hiroyuki Hosokawa, Maile Romero-Wolf, Wen Zhou, Kaori Masuhara, Victoria R. Tobin, Ditsa Levanon, Yoram Groner, and Ellen V. Rothenberg. "Runx1 and Runx3 drive progenitor to T-lineage transcriptome conversion in mouse T cell commitment via dynamic genomic site switching." Proceedings of the National Academy of Sciences 118, no. 4 (January 21, 2021): e2019655118. http://dx.doi.org/10.1073/pnas.2019655118.
Full textAbstract:
Runt domain-related (Runx) transcription factors are essential for early T cell development in mice from uncommitted to committed stages. Single and double Runx knockouts via Cas9 show that target genes responding to Runx activity are not solely controlled by the dominant factor, Runx1. Instead, Runx1 and Runx3 are coexpressed in single cells; bind to highly overlapping genomic sites; and have redundant, collaborative functions regulating genes pivotal for T cell development. Despite stable combined expression levels across pro-T cell development, Runx1 and Runx3 preferentially activate and repress genes that change expression dynamically during lineage commitment, mostly activating T-lineage genes and repressing multipotent progenitor genes. Furthermore, most Runx target genes are sensitive to Runx perturbation only at one stage and often respond to Runx more for expression transitions than for maintenance. Contributing to this highly stage-dependent gene regulation function, Runx1 and Runx3 extensively shift their binding sites during commitment. Functionally distinct Runx occupancy sites associated with stage-specific activation or repression are also distinguished by different patterns of partner factor cobinding. Finally, Runx occupancies change coordinately at numerous clustered sites around positively or negatively regulated targets during commitment. This multisite binding behavior may contribute to a developmental “ratchet” mechanism making commitment irreversible.
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Morita, Ken, Kensho Suzuki, Shintaro Maeda, Yoshihide Mitsuda, Ayaka Yano, Yoshimi Yamada, Hiroki Kiyose, et al. "Cluster Regulation of RUNX Family By "Gene Switch" Triggers a Profound Tumor Regression of Diverse Origins." Blood 128, no. 22 (December 2, 2016): 443. http://dx.doi.org/10.1182/blood.v128.22.443.443.
Full textAbstract:
Abstract Although Runt-related transcription factor 1 (RUNX1), a member of RUNX family and a distant relative of p53, has been generally considered to be a tumor suppressor, a growing body of evidence strongly suggests its pro-oncogenic property in acute myeloid leukemia (AML). Here we demonstrate that switching off RUNX cluster utilizing the newly synthesized compound, which specifically bound to a particular base sequence of DNA, was highly effective against leukemia as well as dismal-prognostic solid tumors arising from diverse origins in vivo. Firstly, to assess the RUNX1 loss in AML cells, we performed shRNA-mediated RUNX1 knockdown experiments. Silencing of RUNX1 stimulated cell cycle arrest at G0/G1 phase and simultaneously induced apoptosis in AML cells bearing wild-type p53. RUNX1 depletion induced remarkable induction of p53 as well as its target gene products and additive knockdown of p53 in these cell lines reverted the phenotype of RUNX1-depletion, indicating that RUNX1 is functionally dependent on proficient p53 pathway. In addition, cycloheximide chase assay revealed that RUNX1 negatively regulates p53 protein in AML cells. In silico data analysis of clinical gene expression array data sets and ChIP-seq experiments using anti-RUNX1 antibody identified 32 candidate genes potentially required for RUNX1-dependent degradation of p53. Among them, we focused on BCL11A and TRIM24, both of which are established mediators of p53 degradation. In accordance with these observations, knockdown of RUNX1 resulted in a significant down-regulation of BCL11A and TRIM24 both at mRNA and protein levels. ChIP-qPCR assay further validated the actual binding of RUNX1 at the promoter regions of these genes, and reintroduction of BCL11A or TRIM24 into RUNX1-silenced AML cells restored their proliferation speed to the control levels. These data suggests that RUNX1 depletion-mediated growth inhibitory effect on leukemia cells depends on p53 activation via transcriptional regulation of BCL11A and TRIM24. Though RUNX1 depletion was highly effective on proliferation of AML cells, a small sub-population of leukemia cells retained the proliferation potential even after the silencing of RUNX1. Since it has been shown that RUNX family member has a redundant function, we next examined the other RUNX family members such as RUNX2 and RUNX3 in RUNX1-knocked down AML cells. Under our tetracycline-inducible shRNA expression system, the expression levels of RUNX1-target genes were decreased at 24 h after RUNX1 knockdown, however, their expression levels were reciprocally increased at 48 h accompanied by increment of RUNX2 and RUNX3 expressions, suggesting that RUNX2 and RUNX3 might compensate for the loss of RUNX1 functions. ChIP-qPCR assay and luciferase reporter experiments confirmed that individual RUNX family member consistently suppressed the promoter activity of the other RUNX members. In accordance with these findings, additional knockdown of RUNX2, RUNX3 or both of them in RUNX1-depleted AML cells effectively repressed RUNX1-target gene expressions and completely suppressed their proliferation. Thus the simultaneous targeting of all RUNX family members as a cluster achieves more stringent control of leukemia cells. Since sequencing analysis of the functional gene alterations of RUNX family members revealed the existence of mutations in a mutual-exclusive manner not only in AML cells but also in various cancers, their functional redundancy in the maintenance of AML cells might be generally accepted. To achieve cluster regulations of RUNX, we conducted a synthesized molecule library screening and succeeded in extracting agents that could irreversibly block the RUNX cluster genes expression profiling through dismantling protein-DNA interactions sequence-specifically. These reagents were highly effective against leukemia as well as dismal-prognostic solid tumors arising from diverse origins in vitro. Furthermore, these reagents were exceptionally well-tolerated in mice and exerted excellent efficacy against xenograft mice models of AML, acute lymphoblastc leukemia, lung and gastric cancers, extending their overall survival periods in vivo. Together, this work identifies the crucial role of RUNX cluster in the maintenance and the progression of cancer cells, and the indicated gene switch technology-dependent its modulation would be a novel strategy to control malignancies. Disclosures No relevant conflicts of interest to declare.
4
Masuda, Tatsuya, Hirohito Kubota, Naoya Sakuramoto, Asuka Hada, Ayaka Horiuchi, Asami Sasaki, Kanako Takeda, et al. "RUNX-NFAT Axis As a Novel Therapeutic Target for AML and T Cell Immunity." Blood 136, Supplement 1 (November 5, 2020): 25–26. http://dx.doi.org/10.1182/blood-2020-143458.
Full textAbstract:
Runt-related transcription factor (RUNX) transcription factors are essential regulators of diverse developmental processes. In mammals, there are three RUNX genes, RUNX1, RUNX2, and RUNX3. All RUNX proteins contain a highly conserved DNA-binding domain, called the runt-homology domain (RHD), which is responsible for DNA-binding and interaction with a partner, core binding factor subunit β (CBFβ). They regulate transcription of target genes, involving hematopoietic differentiation, cell cycle regulation, p53 pathways, and so on. From our previous studies, we assume that compensation mechanism is present among the RUNX family members. RUNX plays pivotal roles in leukemogenesis and inhibition of RUNX has now been widely recognized as a novel strategy in anti-leukemic therapies. However, common mechanism via RUNX in diverse acute myeloid leukemia (AML) remains elusive. Here, we demonstrate that targeting RUNX-nuclear factor of activated T cells 2 (NFATC2) axis is an effective strategy to suppress drug-resistant (DR)-acute promyelocytic leukemia (APL) cells. Silencing of RUNX and NFATC2 in DR-APL cells suppressed cell growth and induced apoptotic cell death. Next, by RNA-seq analysis of several AML patient cohorts, we confirmed that a strong positive correlation between RUNX family (RUNX1,2,3: Pan RUNX) and NFAT family (NFATC1,2,3,4, NFAT5: Pan NFAT) exists not only in APL but also in all hematopoietic malignancies and that AML forms the Pan RUNX high-Pan NFAT high expression cluster. Inspection of the NFATC1-3 promoter revealed the RUNX binding sequence, and direct transcriptionally regulation of NFATC1-3 by RUNX family was confirmed in both chromatin immunoprecipitation (ChIP)-seq analysis and dual luciferase reporter assay. We believe that RUNX-NFAT axis could be an important target in diverse AML. Next, considering the well-established role of RUNX and NFATC2 in T cell immunity, we also apply targeting RUNX-NFATC2 strategy to suppress T cell activation and xenogeneic graft-versus-host disease (GVHD).The expansion of donor T cells requires IL-2, and aGVHD has been defined as a Th1-mediated disease. It is now well known that RUNX, especially RUNX1 and RUNX3 , are highly expressed in T cells, and directly regulate Th1 cytokine genes. As immunosuppressive approach for the prevention or treatment of aGVHD, calcineurin inhibitors, cyclosporine A and tacrolimus, inhibit GVHD by preventing the activation of NFAT, and steroid inhibits transcription of proinflammatory genes. We suppose that targeting RUNX can downregulate NFAT and also cytokine genes in T cell. RUNX1 knockdown and PanRUNX knockdown led to deceased NFATC2 and cytokine gene expression in cytokine-producing Jurkat cell line. It was also confirmed that by inhibiting the RUNX family and suppressing the NFATC2 family at the transcriptional level, the amount of the total NFATC family was significantly reduced compared with the drug that suppresses the nuclear translocation of NFATc2.The importance of RUNX-NFATC2 axis in T cell immunity was also exactly confirmed by the rescue experiments. Finally, to achieve "cluster regulation of RUNX (CROX)" strategy, we have been developing a novel RUNX inhibitor: chlorambucil-conjugated pyrrole-imidazole (PI) polyamides (Chb-M') that targets consensus RUNX-binding sequences, and specifically inhibits binding of RUNX family members. So, Chb-M' can switch off the RUNX target genes efficiently. In diverse AML including APL, core binding factor (CBF)-AML, mixed lineage leukemia (MLL)-rearranged AML, and AML-M0 and so on, Chb-M' was remarkably effective, and suppressed the expression of NFAT family in the protein level and induced apoptotic cell death. ChbM' also had a prominent effect in the AMLPDX model.The importance of RUNX-NFAT axis in AML was confirmed by the pharmacological rescue experiments using phorbol 12-myristate 13-acetate (PMA) and Ionomycin stimulation. Chb-M' also suppressed NFATC2 and cytokine gene expression in peripheral blood mononuclear cells (PBMC) and ameliorated GVHD for xenogeneic GVHD mouse model by transplanting human PBMC into immunodeficient mice. Taken together, we show RUNX could be a novel therapeutic target against diverse AML and GVHD through targeting RUNX-NFAT axis. Disclosures No relevant conflicts of interest to declare.
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Chuang, Linda Shyue Huey, Junichi Matsuo, Daisuke Douchi, Nur Astiana Bte Mawan, and Yoshiaki Ito. "RUNX3 in Stem Cell and Cancer Biology." Cells 12, no. 3 (January 25, 2023): 408. http://dx.doi.org/10.3390/cells12030408.
Full textAbstract:
The runt-related transcription factors (RUNX) play prominent roles in cell cycle progression, differentiation, apoptosis, immunity and epithelial–mesenchymal transition. There are three members in the mammalian RUNX family, each with distinct tissue expression profiles. RUNX genes play unique and redundant roles during development and adult tissue homeostasis. The ability of RUNX proteins to influence signaling pathways, such as Wnt, TGFβ and Hippo-YAP, suggests that they integrate signals from the environment to dictate cell fate decisions. All RUNX genes hold master regulator roles, albeit in different tissues, and all have been implicated in cancer. Paradoxically, RUNX genes exert tumor suppressive and oncogenic functions, depending on tumor type and stage. Unlike RUNX1 and 2, the role of RUNX3 in stem cells is poorly understood. A recent study using cancer-derived RUNX3 mutation R122C revealed a gatekeeper role for RUNX3 in gastric epithelial stem cell homeostasis. The corpora of RUNX3R122C/R122C mice showed a dramatic increase in proliferating stem cells as well as inhibition of differentiation. Tellingly, RUNX3R122C/R122Cmice also exhibited a precancerous phenotype. This review focuses on the impact of RUNX3 dysregulation on (1) stem cell fate and (2) the molecular mechanisms underpinning early carcinogenesis.
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de Bruijn, Marella, and Elaine Dzierzak. "Runx transcription factors in the development and function of the definitive hematopoietic system." Blood 129, no. 15 (April 13, 2017): 2061–69. http://dx.doi.org/10.1182/blood-2016-12-689109.
Full textAbstract:
AbstractThe Runx family of transcription factors (Runx1, Runx2, and Runx3) are highly conserved and encode proteins involved in a variety of cell lineages, including blood and blood-related cell lineages, during developmental and adult stages of life. They perform activation and repressive functions in the regulation of gene expression. The requirement for Runx1 in the normal hematopoietic development and its dysregulation through chromosomal translocations and loss-of-function mutations as found in acute myeloid leukemias highlight the importance of this transcription factor in the healthy blood system. Whereas another review will focus on the role of Runx factors in leukemias, this review will provide an overview of the normal regulation and function of Runx factors in hematopoiesis and focus particularly on the biological effects of Runx1 in the generation of hematopoietic stem cells. We will present the current knowledge of the structure and regulatory features directing lineage-specific expression of Runx genes, the models of embryonic and adult hematopoietic development that provide information on their function, and some of the mechanisms by which they affect hematopoietic function.
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Suzuki, Kensho, Ken Morita, Shintaro Maeda, Hiroki Kiyose, Souichi Adachi, and Yasuhiko Kamikubo. "Paradoxical Enhancement of Leukemogenesis in Acute Myeloid Leukemia Cells with Moderately Attenuated RUNX1 Expressions." Blood 128, no. 22 (December 2, 2016): 2710. http://dx.doi.org/10.1182/blood.v128.22.2710.2710.
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Abstract Although Runt-related transcription factor 1 (RUNX1), a member of RUNX transcription family, is known for its oncogenic role in the development of acute myeloid leukemia (AML), evidence from other groups support the oncosuppressive property of RUNX1 in leukemia cells, casting a question over the bidirectional function of RUNX1 and it is currently highly controversial. Here we report that the dual function of RUNX1 possibly arise from the total level of RUNX family expressions. To examine the precise mechanism of RUNX1 expression in leukemogenesis, we first prepared several tetracycline-inducible short hairpin RNAs (shRNAs) which could attenuate the expressions of RUNX1 at different levels in AML cells (MV4-11 and MOLM-13 cells). Intriguingly, while AML cells transduced with shRNAs which could down-regulate RUNX1 expression below 10% at protein level (sh_Rx1_profound) deteriorated the proliferation speed of AML cells, AML cells transduced with shRNAs which could moderately down-regulate RUNX1 expression to 70% at protein level (sh_Rx1_moderate) paradoxically promoted the cell cycle progression and doubled the growth rate of AML cells. Besides, RUNX1-moderately expressing AML patient cohort exhibited the worse outcome compared to RUNX1-high or RUNX1-low expressing cohorts (n = 187), indicating an underlying mechanism that confer growth advantage to AML cells with moderately inhibited RUNX1 expressions. To further investigate the correspondent gene in this paradoxical enhancement of oncogenesis in sh_Rx1_moderate-transduced AML cells, we performed comprehensive gene expression array and extracted genes that are highly up-regulated in RUNX1 moderate inhibition and down-regulated in AML cells transduced with sh_Rx1_profound. We hereafter focused on the top-listed gene glutathione S-transferase alpha 2 (GSTA2) and addressed the interaction of RUNX1 and GSTA2 and their functions in AML cells. Real time quantitative PCR (RT-qPCR) and immunoblotting revealed that the expression of GSTA2 was actually up-regulated in sh_Rx1_moderate-transduced AML cells and down-regulated in AML cells transduced with sh_Rx1_profound. Interestingly, equivalent level of compensatory up-regulation of RUNX2 and RUNX3 were observed in sh_Rx1_moderate- and sh_Rx1_profound-transduced AML cells, creating an absolute gap in the expression of total amount of RUNX (RUNX1 + RUNX2 + RUNX3), which was confirmed by RT-qPCR (total amount of RUNX expressions were estimated by primers amplifying the specific sequence common to all RUNX family members). Luciferase reporter assay of GSTA2 promoter and chromatin immunoprecipitation (ChIP) assay in the proximal promoter region of GSTA2 gene proved the association of RUNX family members with this genomic region. These results indicated that total amount of RUNX family expressions modulate the expression of GSTA2 in AML cells, which might results in a paradoxical outbursts of RUNX1 moderately-inhibited AML cells. Since GSTA2 catabolizes and scavenges free radicals such as hydrogen peroxide (H2O2), and decreased intracellular free radicals promote acceleration of cell cycle progression, we next measured the intracellular accumulation of H2O2 in RUNX1 inhibited AML cells. As we have expected, intracellular amount of H2O2 was decreased in sh_Rx1_moderate-transduced AML cells and increased in AML cells transduced with sh_Rx1_profound. Additive transduction of sh_RNAs targeting GSTA2 to AML cells with sh_Rx1_moderate reverted the proliferation speed to the control level, underpinning that growth advantage of moderate RUNX1 inhibition could be attributed to the GSTA2 overexpressions. Taken together, these findings indicate that moderately attenuated RUNX1 expressions paradoxically enhance leukemogenesis in AML cells through intracellular environmental change via GSTA2, which could be a novel therapeutic target in anti-leukemia strategy. Disclosures No relevant conflicts of interest to declare.
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Klunker, Sven, Mark M. W. Chong, Pierre-Yves Mantel, Oscar Palomares, Claudio Bassin, Mario Ziegler, Beate Rückert, et al. "Transcription factors RUNX1 and RUNX3 in the induction and suppressive function of Foxp3+ inducible regulatory T cells." Journal of Experimental Medicine 206, no. 12 (November 16, 2009): 2701–15. http://dx.doi.org/10.1084/jem.20090596.
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Forkhead box P3 (FOXP3)+CD4+CD25+ inducible regulatory T (iT reg) cells play an important role in immune tolerance and homeostasis. In this study, we show that the transforming growth factor-β (TGF-β) induces the expression of the Runt-related transcription factors RUNX1 and RUNX3 in CD4+ T cells. This induction seems to be a prerequisite for the binding of RUNX1 and RUNX3 to three putative RUNX binding sites in the FOXP3 promoter. Inactivation of the gene encoding RUNX cofactor core-binding factor-β (CBFβ) in mice and small interfering RNA (siRNA)-mediated suppression of RUNX1 and RUNX3 in human T cells resulted in reduced expression of Foxp3. The in vivo conversion of naive CD4+ T cells into Foxp3+ iT reg cells was significantly decreased in adoptively transferred CbfbF/F CD4-cre naive T cells into Rag2−/− mice. Both RUNX1 and RUNX3 siRNA silenced human T reg cells and CbfbF/F CD4-cre mouse T reg cells showed diminished suppressive function in vitro. Circulating human CD4+ CD25high CD127− T reg cells significantly expressed higher levels of RUNX3, FOXP3, and TGF-β mRNA compared with CD4+CD25− cells. Furthermore, FOXP3 and RUNX3 were colocalized in human tonsil T reg cells. These data demonstrate Runx transcription factors as a molecular link in TGF-β–induced Foxp3 expression in iT reg cell differentiation and function.
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Ando, Kiyohiro, and Akira Nakagawara. "The RUNX Family Defines Trk Phenotype and Aggressiveness of Human Neuroblastoma through Regulation of p53 and MYCN." Cells 12, no. 4 (February 8, 2023): 544. http://dx.doi.org/10.3390/cells12040544.
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The Runt-related transcription factor (RUNX) family, which is essential for the differentiation of cells of neural crest origin, also plays a potential role in neuroblastoma tumorigenesis. Consecutive studies in various tumor types have demonstrated that the RUNX family can play either pro-tumorigenic or anti-tumorigenic roles in a context-dependent manner, including in response to chemotherapeutic agents. However, in primary neuroblastomas, RUNX3 acts as a tumor-suppressor, whereas RUNX1 bifunctionally regulates cell proliferation according to the characterized genetic and epigenetic backgrounds, including MYCN oncogenesis. In this review, we first highlight the current knowledge regarding the mechanism through which the RUNX family regulates the neurotrophin receptors known as the tropomyosin-related kinase (Trk) family, which are significantly associated with neuroblastoma aggressiveness. We then focus on the possible involvement of the RUNX family in functional alterations of the p53 family members that execute either tumor-suppressive or dominant-negative functions in neuroblastoma tumorigenesis. By examining the tripartite relationship between the RUNX, Trk, and p53 families, in addition to the oncogene MYCN, we endeavor to elucidate the possible contribution of the RUNX family to neuroblastoma tumorigenesis for a better understanding of potential future molecular-based therapies.
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Zhao, Ling, Jennifer L. Cannons, Lucio H. Castilla, Pamela L. Schwartzberg, and Pu Paul Liu. "The Role of CBFβ in T Cell Development." Blood 104, no. 11 (November 16, 2004): 3234. http://dx.doi.org/10.1182/blood.v104.11.3234.3234.
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Abstract Core binding factor β (Cbfβ) is a transcription factor that heterodimerizes with Runx (Cbfα) family members, thereby stabilizing the interaction between the Runx proteins and DNA. Genetically manipulated mouse models of Runx and Cbfb genes have demonstrated their critical functions in hematopoiesis (Runx1, Runx3 and Cbfb), bone formation (Runx2, Cbfb), proliferation of gastrointestinal epithelia (Runx3) and differentiation of dorsal root ganglion cells (Runx3). Studies on T cell development showed that Runx1 and Runx3 repress CD4 expression at different stages of development. In addition, Runx 1 and Runx 3 are required for CD8 T cell development during thymopoiesis. No defects were found when Runx2 was inactivated, even though it is expressed throughout T cell development. We have previously generated a knock-in mouse model expressing the Cbfb-MYH11 fusion gene (which is created by inv(16)(p13; q22) in human AML M4Eo). Heterozygous knock-in mice had a phenotype identical to that of the Cbfb and Runx1 null mice (embryonic lethality), suggesting that the fusion gene Cbfb-MYH11 functions in a dominant-negative manner. In order to study the function of Cbfb gene in T cell development, we used a mouse line with floxed exons 5 and 6 of Cbfb inserted 5′ to the Cbfb-MYH11 fusion cassette, which produced pseudo-normal mice (loxKI). By crossing the loxKI mice with mice expressing the Cre gene under the control of the T cell-specific Lck promoter (LckCre), we generated LckCre-loxKI double positive mice, in which the floxed exon 5 and 6 were deleted and Cbfb-MYH11 re-expressed only in the thymus when Lck started to express. The LckCre-loxKI mice were viable. However, their thymic development was severely impaired: The size of the thymuses in the mutant mice was about half the normal size, and the total number of thymocytes in the mutant mice was 10–20-fold reduced. FACS analysis of thymocytes from 4 to 12 week old mice showed a developmental blockade at the CD4/CD8-double negative (DN) stage, which was characterized by lower percentage of double positive cells and higher percentage of double negative cells. In addition, the CD4: CD8 ratio was altered. Furthermore, the mature T cell population size in the spleen of the mutant mice was lower than that of the control mice. Our preliminary data suggested that Cbfb plays an important role in T cell development. The mechanism through which Cbfb affects the T cell development is currently under investigation. It is likely that the phenotype reflects the combined effect of missing all three Runx genes, since the phenotype described here is more severe than either Runx1 or Runx3 null alone.
Dissertations / Theses on the topic "RUNX"
1
LeBlanc, Kimberly T. "Runx Expression in Normal and Osteoarthritic Cartilage: Possible Functions of Runx Proteins in Chondrocytes: A Dissertation." eScholarship@UMMS, 2013. https://escholarship.umassmed.edu/gsbs_diss/655.
Full textAbstract:
The Runx family of transcription factors supports cell fate determination, cell cycle regulation, global protein synthesis control, and genetic as well as epigenetic regulation of target genes. Runx1, which is essential for hematopoiesis; Runx2, which is required for osteoblast differentiation; and Runx3, which is involved in neurologic and gut development; are expressed in the growth plate during chondrocyte maturation, and in the chondrocytes of permanent cartilage structures. While Runx2 is known to control genes that contribute to chondrocyte hypertrophy, the functions of Runx1 and Runx3 during chondrogenesis and in cartilage tissue have been less well studied.
The goals of this project were to characterize expression of Runx proteins in articular cartilage and differentiating chondrocytes and to determine the contribution of Runx1 to osteoarthritis (OA). Here, the expression pattern of Runx1 and Runx2 was characterized in normal bovine articular cartilage. Runx2 is expressed at higher levels in deep zone chondrocytes, while Runx1 is primarily expressed in superficial zone chondrocytes, which is the single cell layer that lines the surface of articular cartilage. Based on this finding, the hypothesis was tested that Runx1 is involved in osteoarthritis, which is a disease characterized by degradation of articular cartilage and changes in chondrocytes. These studies showed that Runx1 is upregulated in articular cartilage explants in response to mechanical compression. Runx1 was also expressed in chondrocytes found at the periphery of OA lesions in the articular cartilage of mice that underwent an OA-inducing surgery. Runx1 was also upregulated in cartilage explants of human osteoarthritic knees, and IHC data showed that Runx1 is mainly expressed in chondrocyte “clones” characteristic of OA.
To ascertain the potential function of the upregulation of Runx1 in these cartilage stress conditions and disease states, the hypothesis was tested that Runx1 is upregulated in very specific chondrocyte populations in response to the cartilage damage in osteoarthritis. These studies addressed the properties of these cells that related to functions in cell growth and differentiation. In both the surface layer of normal articular cartilage, and in OA cartilage, Runx1 expression by IF co-localized with markers of mesenchymal progenitor cells, as well as markers of proliferation Ki-67 and PCNA. This finding indicated that Runx1 is found in a population of cells that represent a proliferative population of mesenchymal progenitor cells in osteoarthritis.
To further address Runx1 function and identify downstream targets of Runx proteins, a promoter analysis of genes that are known to be either downregulated or upregulated during chondrocyte maturation was done. These studies found that many of these genes have 1 or more Runx binding sites within 2kb of their transcription start site, indicating that they are potential downstream Runx target genes.
Lastly, some preliminary experiments were done to characterize novel roles of Runx proteins in the chondrocyte. Runx proteins have been shown to epigenetically regulate their target genes by remaining bound to them throughout mitosis, “poising” them for transcription upon exit from mitosis. The hypothesis that Runx proteins also function by remaining bound to their target genes throughout mitosis in chondrocytes was tested. It was demonstrated by immunofluorescense imaging of Runx proteins on metaphase chromosomes of ATDC5 cells, that Runx2 remains bound to chromosomes during mitosis.
Cell proliferation and hypertrophy are both linked to increases in protein synthesis. Runx factors, which regulate rates of global protein synthesis, are expressed in both proliferating and hypertrophic chondrocytes. Thus, it was hypothesized that Runx proteins regulate rates of global protein synthesis during chondrocyte maturation. These studies showed that the overexpression of Runx proteins in a chondrocyte cell line (ATDC5) did not affect protein synthesis rates or levels of protein synthesis machinery. Additionally, Runx proteins did not affect proliferation rates in this chondrocyte cell line.
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LeBlanc, Kimberly T. "Runx Expression in Normal and Osteoarthritic Cartilage: Possible Functions of Runx Proteins in Chondrocytes: A Dissertation." eScholarship@UMMS, 2002. http://escholarship.umassmed.edu/gsbs_diss/655.
Full textAbstract:
The Runx family of transcription factors supports cell fate determination, cell cycle regulation, global protein synthesis control, and genetic as well as epigenetic regulation of target genes. Runx1, which is essential for hematopoiesis; Runx2, which is required for osteoblast differentiation; and Runx3, which is involved in neurologic and gut development; are expressed in the growth plate during chondrocyte maturation, and in the chondrocytes of permanent cartilage structures. While Runx2 is known to control genes that contribute to chondrocyte hypertrophy, the functions of Runx1 and Runx3 during chondrogenesis and in cartilage tissue have been less well studied.
The goals of this project were to characterize expression of Runx proteins in articular cartilage and differentiating chondrocytes and to determine the contribution of Runx1 to osteoarthritis (OA). Here, the expression pattern of Runx1 and Runx2 was characterized in normal bovine articular cartilage. Runx2 is expressed at higher levels in deep zone chondrocytes, while Runx1 is primarily expressed in superficial zone chondrocytes, which is the single cell layer that lines the surface of articular cartilage. Based on this finding, the hypothesis was tested that Runx1 is involved in osteoarthritis, which is a disease characterized by degradation of articular cartilage and changes in chondrocytes. These studies showed that Runx1 is upregulated in articular cartilage explants in response to mechanical compression. Runx1 was also expressed in chondrocytes found at the periphery of OA lesions in the articular cartilage of mice that underwent an OA-inducing surgery. Runx1 was also upregulated in cartilage explants of human osteoarthritic knees, and IHC data showed that Runx1 is mainly expressed in chondrocyte “clones” characteristic of OA.
To ascertain the potential function of the upregulation of Runx1 in these cartilage stress conditions and disease states, the hypothesis was tested that Runx1 is upregulated in very specific chondrocyte populations in response to the cartilage damage in osteoarthritis. These studies addressed the properties of these cells that related to functions in cell growth and differentiation. In both the surface layer of normal articular cartilage, and in OA cartilage, Runx1 expression by IF co-localized with markers of mesenchymal progenitor cells, as well as markers of proliferation Ki-67 and PCNA. This finding indicated that Runx1 is found in a population of cells that represent a proliferative population of mesenchymal progenitor cells in osteoarthritis.
To further address Runx1 function and identify downstream targets of Runx proteins, a promoter analysis of genes that are known to be either downregulated or upregulated during chondrocyte maturation was done. These studies found that many of these genes have 1 or more Runx binding sites within 2kb of their transcription start site, indicating that they are potential downstream Runx target genes.
Lastly, some preliminary experiments were done to characterize novel roles of Runx proteins in the chondrocyte. Runx proteins have been shown to epigenetically regulate their target genes by remaining bound to them throughout mitosis, “poising” them for transcription upon exit from mitosis. The hypothesis that Runx proteins also function by remaining bound to their target genes throughout mitosis in chondrocytes was tested. It was demonstrated by immunofluorescense imaging of Runx proteins on metaphase chromosomes of ATDC5 cells, that Runx2 remains bound to chromosomes during mitosis.
Cell proliferation and hypertrophy are both linked to increases in protein synthesis. Runx factors, which regulate rates of global protein synthesis, are expressed in both proliferating and hypertrophic chondrocytes. Thus, it was hypothesized that Runx proteins regulate rates of global protein synthesis during chondrocyte maturation. These studies showed that the overexpression of Runx proteins in a chondrocyte cell line (ATDC5) did not affect protein synthesis rates or levels of protein synthesis machinery. Additionally, Runx proteins did not affect proliferation rates in this chondrocyte cell line.
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Whiteman, Hannah Juliette. "RUNX expression and function in human B cells." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422343.
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Chen, Aichun. "Regulation of lozenge transcription factor activity and blood cell development by MLF and its partner DnaJ-1." Thesis, Toulouse 3, 2017. http://www.theses.fr/2017TOU30064/document.
Full textAbstract:
L'hématopoïèse est le processus de formation des cellules sanguines différenciées à partir de cellules souches hématopoïétiques. Ce processus est étroitement contrôlé par l'intégration de signaux de développementaux et homéostatiques pour assurer une production équilibrée des différents types de cellules sanguines. Au niveau moléculaire, la régulation de ce processus est médiée par un certain nombre de facteurs de transcription, en particulier par les membres de la famille RUNX. Ainsi, des mutations affectant les membres de cette famille peuvent entrainer une déréglementation du programme de différenciation hématopoïétique et causer des hémopathies, dont des leucémies. D'une manière intrigante, de nombreux régulateurs de la transcription et des voies de signalisation contrôlant le développement des cellules sanguines sont évolutivement conservés des humains à Drosophila melanogaster, qui est donc utilisée comme organisme modèle pour étudier les mécanismes sous-jacents à la spécification des lignages sanguins et au contrôle de l'homéostasie des cellules sanguines. Les membres de la famille Myeloid Leukemia Factor (MLF) ont été impliqués dans l'hématopoïèse et dans la transformation oncogénique des cellules sanguines, mais leur fonction et leur mécanisme d'action moléculaire restent insaisissables. Des travaux précédents chez la Drosophile ont montré que MLF stabilise le facteur de transcription de type RUNX Lozenge (LZ) et contrôle le nombre de cellules sanguines LZ+. Au cours de ma thèse, j'ai cherché à déchiffrer le mécanisme moléculaire d'action de MLF sur Lozenge dans les cellules sanguines. Par une approche protéomique puis par des expériences de co-immunoprécipitation dans les cellules de Drosophile Kc167, nous avons identifié le co-chaperon de type Hsp40 DnaJ-1, et son partenaire le chaperon Hsc70-4, comme deux partenaires de MLF. De façon importante, nous avons montré que l'inhibition de l'expression de DnaJ-1 ou de Hsc70-4 dans les cellules Kc167 induit une réduction du niveau de protéine Lozenge et une diminution de sa capacité à activer la transcription très semblable à celles observées suite à l'inhibition de l'expression de MLF. De plus, la sur-expression de mutants de DnaJ-1 incapables d'activer le chaperon Hsc70-4 entraîne aussi une réduction du niveau de Lozenge et de sa capacité de transactivation et des expériences de coimmunoprécipitation montrent que Lozenge interagit avec MLF, DnaJ-1 et Hsc70-4. Nos résultats suggèrent donc que MLF agit au sein d'un complexe chaperon composé de DnaJ-1 et Hsc70-4 pour contrôler le niveau de Lozenge. En utilisant différents mutants de MLF ou DnaJ-1, nous avons montré que MLF et DnaJ-1 interagissent ensemble et avec Lozenge via des domaines phylogénétiquement conservés. D'autre part, des expériences de GST " pull down " in vitro suggèrent que ces trois protéines peuvent interagir ensemble directement. Nous proposons donc que MLF et DnaJ-1 contrôlent le niveau de protéine Lozenge en interagissant avec elle et en favorisant son repliement et/ou sa solubilité via l'activité chaperon de Hsc70-4. En parallèle, nous avons étudié la fonction de DnaJ-1 in vivo dans le développement des cellules sanguines de la Drosophile. Nos résultats montrent que, comme mlf, la perte de dnaj-1 s'accompagne d'une augmentation de la taille et du nombre des cellules sanguines LZ+, ainsi que d'une hyperactivation de la voie de signalisation Notch dans ces cellules. Nos résultats suggèrent que des hauts niveaux de Lozenge sont nécessaires pour contrôler le nombre et la taille des cellules LZ+ et pour inhiber l'expression de Notch. Nous proposons que le complexe MLF/DnaJ-1 contrôle le développement du lignage LZ+ en régulant le niveau de protéine Lozenge, et ainsi le niveau d'activité de la voie Notch. En conclusion, nos résultats ont mis à jour un lien fonctionnel entre MLF, le co-chaperon de type Hsp40 DnaJ-1 et un facteur de transcription de type RUNX, qui pourrait être conservé dans d'autres espècesHematopoiesis is the process of formation of fully differentiated blood cells from hematopoietic stem cells (HSCs). This process is tightly controlled by the integration of developmental and homeostatic signals to ensure the generation of an appropriate number of each blood cell type. At the molecular level, the regulation of this developmental process is mediated by a number of transcription factors, especially by members of the RUNX family, and mutations affecting these factors are at the origin of numerous hemopathies, including leukemia. Intriguingly, many transcriptional regulators and signaling pathways controlling blood cell development are evolutionarily conserved from humans to Drosophila melanogaster. Hence, the fruit fly has become a potent and simplified model to study the mechanisms underlying the specification of blood cell lineages and the regulation of blood cell homeostasis. Members of the Myeloid Leukemia Factor (MLF) family have been implicated in hematopoiesis and in oncogenic blood cell transformation, but their function and molecular mechanism of action remain elusive. Previous work in Drosophila showed that MLF stabilizes the RUNX transcription factor Lozenge (LZ) and controls the number of LZ+ blood cells. During my PhD, I sought to further decipher the molecular mechanism of action of MLF on Lozenge during blood cell development. Using a proteomic approach in Drosophila Kc167 cells, we identified the Hsp40 co-chaperone family member DnaJ-1 and its chaperone partner Hsc70-4 as two partners of MLF. These interactions were confirmed by co-immunoprecipitations and in vitro pull-down assays. Importantly, we found that knocking down DnaJ-1 or Hsc70-4 expression in Kc167 cells caused a reduction in the level of Lozenge protein and a concomitant decrease in Lozenge transactivation activity, which were very similar to those caused by MLF knock-down. Similarly, over-expression of two DnaJ-1 mutants that are unable to stimulate the chaperone activity of Hsc70-4 also decreased Lozenge level and impaired its capacity to activate transcription. These results suggest that MLF could act within a chaperone complex composed of DnaJ-1 and Hsc70-4 to control Lozenge stability and activity. Along that line, we showed by co-immunoprecipitation that Lozenge interacts with MLF, DnaJ-1 and Hsc70-4, respectively. Using various truncated mutants of MLF or DnaJ-1, we showed that MLF and DnaJ-1 interact and together with Lozenge through their conserved MLF homology domain (MHD) and C-terminal region, respectively. Furthermore, in vitro GST pull-down assays suggested that the interactions between MLF, DnaJ-1 and Lozenge are direct. Thus, we propose that MLF and DnaJ-1 control Lozenge protein level by interacting with it and by promoting its folding and/or solubility via the Hsc70 chaperone machinery. In parallel, we assessed DnaJ-1 function in Drosophila blood cells in vivo using a null allele of dnaj-1 generated by CRISPR/Cas9 technique. We found that, like mlf, dnaj-1 mutation leads to an increase in the number and size of LZ+ blood cells, as well as to an over-activation of the Notch signaling pathway in these cells. Moreover, our data suggested that high levels of active Lozenge are required to control the number and size of LZ+ blood cells, and to down-regulate Notch expression. We propose that the MLF/DnaJ-1 complex controls LZ+ blood cell development in vivo by regulating Lozenge protein level/activity and thereby Notch pathway activation. In sum, our results establish a functional link between MLF, the Hsp40 co-chaperone DnaJ-1 and the RUNX transcription factor Lozenge, which could be conserved in other species
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Antony-Debré, Iléana. "Fpd/aml : diagnostic et modélisation d'anomalies de Runx 1." Paris 7, 2013. http://www.theses.fr/2013PA077049.
Full textAbstract:
La maladie FPD/AML (thrombopénie familiale avec prédisposition aux leucémies aiguës myéloïdes) est due à des anomalies constitutives de RUNX1, facteur de transcription indispensable à l'hématopoïèse définitive. Dans un premier travail, nous avons proposé un nouveau moyen diagnostique des altérations de RUNX1. La myosine MYH10, normalement réprimée par RUNX1 au cours de la mégacaryopoïèse, persiste dans les plaquettes de patients FPD/AML contrairement aux patients atteints d'autres thrombopénies constitutionnelles, à l'exception des patients Paris-Trousseau. Ce nouvel outil diagnostique peut permettre également d'identifier des mutations acquises de RUNX1 dans la leucémie myélomonocytaire chronique. Nous avons ensuite modélisé la maladie FPD/AML en dérivant des cellules souches pluripotentes induites (iPSC) à partir de fibroblastes de plusieurs patients FPD/AML, porteurs de différentes anomalies de RUNX1. Nous avons reproduit les phénotypes observés chez les patients avec des défauts de génération du compartiment mégacaryocytaire et de plaquettogenèse pour toutes les lignées ; et une amplification du compartiment granulo-monocytaire uniquement avec les lignées porteuses de la mutation prédisposant à la leucémie. Nous avons mis en évidence, pour la première fois, un défaut de génération du compartiment érythrocytaire primitif embryonnaire. Ces résultats ont été confirmés en utilisant une lignée de cellules souches embryonnaires transduite par un shARN dirigé contre RUNX1. Notre modèle est donc validé, et pourra être utilisé dans le futur pour identifier de nouveaux mécanismes impliqués dans la mégacaryopoïèse et dans la leucémogenèseFPD/AML (familial platelet disorder with predisposition to acute myeloid leukemia) results from constitutive alterations of RUNX1, a hematopoietic transcription factor essential to definitive hematopoiesis. In the first part of our work, we proposed a new diagnostic test to detect RUNX1 alterations. We showed that MYH10, which is regulated negatively by RUNX1 during megakaryopoiesis, persisted in platelets from FPD/AML patients. MYHIO persistence was not detected in platelets from patients with other constitutional thrombocytopenia, except from patients with Paris-Trousseau syndrome. This new test could be used also to detect RUNX1 alterations in acquired haematological disorders like chronic myelomonocytic leukemia. In a second work, we generated induced pluripotent stem cells (iPSC) from fibroblasts of FPD/AML patients with different RUNX1 alterations, in order to model the pathology. We reproduced the phenotype already described in patients with defect in megakaryocytic lineage whatever RUNX1 alterations and increase in granulo-monocytic compartment only with the mutation which predisposes to leukemia. We highlighted for the first time that RUNX1 is necessary also for erythroid lineage. We confirmed these results after RUNX1 knock down in an embryonic stem cell line. In conclusion we validated our model and now we can use it to study the mechanisms leading to dysmegakaryopoiesis and predisposition to leukemia in FPD/AML patients
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Pande, Sandhya. "Regulation of Runx Proteins in Human Cancers: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/559.
Full textAbstract:
Runt related transcription factors (Runx) play an important role in mammalian development by regulating the expression of key genes involved in cell proliferation, differentiation and growth. The work described in this thesis details the mechanisms by which the activity of two members of this family are regulated in human cells. Chapter One provides a brief introduction of Runx transcription factors.
Chapter Two describes the regulation of Runx2 protein by the PI3 kinase/Akt pathway in human breast cancer cells. The PI3 kinase/Akt pathway is one of the major signal transduction pathways through which growth factors influence cell proliferation and survival. It is also one of the most frequently dysregulated pathways in human cancers. We identify Runx2 protein, a key regulator of breast cancer invasion as a novel substrate of Akt kinase and map residues of Runx2 that are phosphorylated by Akt in breast cancer cells. Our results show that phosphorylation by Akt increases the binding of Runx2 protein to its target gene promoters and we identify the phosphorylation events that enhance DNA binding of Runx2. Our work establishes Runx2 protein as a critical effecter downstream of Akt that regulates breast cancer invasion.
In Chapter Three we describe the subnuclear localization of the tumor suppressor protein Runx3 during interphase and mitosis. We find that similar to other Runx family members, Runx3 protein resides in nuclear matrix associated foci during interphase. We delineate a subnuclear targeting signal that directs Runx3 to these nuclear matrix associated foci. Our work establishes that this association of Runx3 protein with the nuclear matrix plays a vital role in regulating its transcriptional activity.
Chromatin immunoprecipitation results show that Runx3 occupies rRNA promoters during interphase. We also find that Runx3 remains associated with chromosomes during mitosis and localizes with nucleolar organizing regions (NORs), reflecting an interaction with epigenetic potential.
This thesis provides novel insights into various mechanisms by which cells regulate the activity of Runx proteins.
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Stephens, Alexandre, and N/A. "Genetic and Functional Characterization of RUNX2." Griffith University. School of Medical Science, 2007. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20070823.100953.
Full textAbstract:
RUNX2 belongs to the RUNT domain family of transcription factors of which three have been identified in humans (RUNX1, RUNX2 and RUNX3). RUNX proteins are vital for metazoan development and participate in the regulation of cellular differentiation and cell cycle progression (Coffman, 2003). RUNX2 is required for proper bone formation by driving the differentiation of osteoblasts from mesenchymal progenitors during development (Ducy et al, 1997; Komori et al, 1997; Otto et al, 1997). RUNX2 is also vital for chondrocyte maturation by promoting the differentiation of chondrocytes to the hypertrophic phenotype (Enomoto et al, 2000). The consequences of completely disrupting the RUNX2 locus in mice provided compelling and conclusive evidence for the biological importance of RUNX2 where knockout mice died shortly after birth with a complete lack of bone formation (Komori et al, 1997; Otto et al, 1997). A further indication of the requisite role of RUNX2 in skeletal development was the discovery that RUNX2 haploinsufficiency in humans and mice caused the skeletal syndrome Cleidocranial Dysplasia (CCD) (Mundlos et al, 1997; Lee et al, 1997). A unique feature of RUNX2 is the consecutive polyglutamine and polyalanine tracts (Q/A domain). Mutations causing CCD have been observed in the Q/A domain of RUNX2 (Mundlos et al, 1997). The Q/A domain is an essential part of RUNX2 and participates in transactivation function (Thirunavukkarasu et al, 1998). Previous genotyping studies conducted in our laboratory identified several rare RUNX2 Q/A variants in addition to a frequently occurring 18 base pair deletion of the polyalanine tract termed the 11Ala allele. Analysis of serum parameters in 78 Osteoarthritis patients revealed the 11Ala allele was associated with significantly decreased osteocalcin. Furthermore, analysis of 11Ala allele frequencies within a Geelong Osteoporosis Study (GOS) fracture cohort and an appropriate age matched control group revealed the 11Ala allele was significantly overrepresented in fracture cases indicating an association with increased fracture risk. To further investigate the 11Ala allele and rare Q/A variants, 747 DNA samples from the Southeast Queensland bone study were genotyped using PCR and PAGE. The experiment served two purposes: 1) to detect additional rare Q/A variants to enrich the population of already identified mutants and 2) have an independent assessment of the effect of the 11Ala allele on fracture to either support or refute our previous observation which indicated the 11Ala allele was associated with an increased risk of fracture in the GOS. From the 747 samples genotyped, 665 were WT, 76 were heterozygous for the 11Ala allele, 5 were homozygous for the 11Ala allele and 1 was heterozygous for a rare 21 bp deletion of the polyglutamine tract. Chi-square analysis of RUNX2 genotype distributions within fracture and non-fracture groups in the Southeast Queensland bone study revealed that individuals that carried at least one copy of the 11Ala allele were enriched in the fracture group (p = 0.16, OR = 1.712). The OR of 1.712 was of similar magnitude to the OR observed in the GOS case-control investigation (OR = 1.9) providing support for the original study. Monte-Carlo simulations were used to combine the results from the GOS and the Southeast Queensland bone study. The simulations were conducted with 10000 iterations and demonstrated that the maximum probability of obtaining both study results by chance was less than 5 times in two hundred (p < 0.025) suggesting that the 11Ala allele of RUNX2 was associated with an increased fracture risk. The second element of the research involved the analysis of rare RUNX2 Q/A variants identified from multiple epidemiological studies of bone. Q/A repeat variants were derived from four populations: the GOS, an Aberdeen cohort, CAIFOS and a Sydney twin study. Collectively, a total of 20 rare glutamine and one alanine variants were identified from 4361 subjects. All RUNX2 Q/A variants were heterozygous for a mutant allele and a wild type allele. Analysis of incident fracture during a five year follow up period in the CAIFOS revealed that Q-variants (n = 8) were significantly more likely to have fractured compared to non-carriers (p = 0.026, OR 4.932 95% CI 1.2 to 20.1). Bone density data as measured by quantitative ultrasound was available for CAIFOS. Analysis of BUA and SOS Z-scores revealed that Q-repeat variants had significantly lower BUA (p = 0.031, mean Z-score of -0.79) and a trend for lower SOS (p = 0.190, mean Z-score of -0.69). BMD data was available for all four populations. To normalize the data across the four studies, FN BMD data was converted into Z-scores and the effect of the Q/A variants on BMD was analysed using a one sample approach. The analysis revealed Q/A variants had significantly lower FN BMD (p = 0.0003) presenting with a 0.65 SD decrease. Quantitative transactivation analysis was conducted on RUNX2 proteins harbouring rare glutamine mutations and the 11Ala allele. RUNX2 proteins containing a glutamine deletion (16Q), a glutamine insertion (30Q) and the 11Ala allele were overexpressed in NIH3T3 and HEK293 cells and their ability to transactivate a known target promoter was assessed. The 16Q and 30Q had significantly decreased reporter activity compared to WT in NIH3T3 cells (p = 0.002 and 0.016, for 16Q and 30Q, respectively). In contrast 11Ala RUNX2 did not show significantly different promoter activation potential (p = 0.54). Similar results were obtained in HEK293 cells where both the 16Q and 30Q RUNX2 displayed decreased reporter activity (p=0.007 and 0.066 for 16Q and 30Q respectively) whereas the 11Ala allele had no material effect on RUNX2 function (p = 0.20). The RUNX2 gene target reporter assay provided evidence to suggest that variation within the glutamine tract of RUNX2 was capable of altering the ability of RUNX2 to activate a known target promoter. In contrast, the 11Ala allele showed no variation in RUNX2 activity. The third feature of the research served the purpose of identifying potential RUNX2 gene targets with particular emphasis on discovering genes cooperatively regulated by RUNX2 and the powerful bone promoting agent BMP2. The experiment was conducted by creating stably transfected NIH3T3 cells lines overexpressing RUNX2 or BMP2 or both RUNX2 and BMP2. Microarray analysis revealed very few genes were differentially regulated between standard NIH3T3 cells and cells overexpressing RUNX2. The results were confirmed via RT-PCR analysis which demonstrated that the known RUNX2 gene targets Osteocalcin and Matrix Metalloproteinase-13 were modestly induced 2.5 fold (p = 0.00017) and 2.1 fold (p = 0.002) respectively in addition to identifying only two genes (IGF-II and SCYA11) that were differentially regulated greater than 10 fold. IGF-II and SYCA11 were significantly down-regulated 27.6 fold (p = 1.95 x 10-6) and 10.1 fold (p = 0.0002) respectively. The results provided support for the notion that RUNX2 on its own was not sufficient for optimal gene expression and required the presence of additional factors. To discover genes cooperatively regulated by RUNX2 and BMP2, microarray gene expression analysis was performed on standard NIH3T3 cells and NIH3T3 cells stably transfected with both RUNX2 and BMP2. Comparison of the gene expression profiles revealed the presence of a large number of differentially regulated genes. Four genes EHOX, CCL9, CSF2 and OSF-1 were chosen to be further characterized via RT-PCR. Sequential RT-PCR analysis on cDNA derived from control cells and cells stably transfected with either RUNX2, BMP2 or both RUNX2/BMP2 revealed that EHOX and CSF2 were cooperatively induced by RUNX2 and BMP2 whereas CCL9 and OSF-1 were suppressed by BMP2. The overexpression of both RUNX2 and BMP2 in NIH3T3 fibroblasts provided a powerful model upon which to discover potential RUNX2 gene targets and also identify genes synergistically regulated by BMP2 and RUNX2. The fourth element of the research investigated the role of RUNX2 in the ascorbic acid mediated induction of MMP-13 mRNA. The study was carried out using NIH3T3 cell lines stably transfected with BMP2, RUNX2 and both BMP2 and RUNX2. The cell lines were grown to confluence and subsequently cultured for a further 12 days in standard media or in media supplemented with AA. RT-PCR analysis was used to assess MMP-13 mRNA expression. The RT-PCR results demonstrated that AA was not sufficient for inducing MMP-13 mRNA in NIH3T3 cells. In contrast RUNX2 significantly induced MMP-13 levels 85 fold in the absence of AA (p = 0.0055) and upregulated MMP-13 mRNA levels 254 fold in the presence of AA (p = 0.0017). The results demonstrated that RUNX2 was essential for the AA mediated induction of MMP-13 mRNA in NIH3T3 cells. The effect of BMP2 on MMP-13 expression was also investigated. BMP2 induced MMP-13 mRNA transcripts a modest 3.8 fold in the presence of AA (p = 0.0027). When both RUNX2 and BMP2 were overexpressed in the presence of AA, MMP-13 mRNA levels were induced a massive 4026 fold (p = 8.7 x 10-4) compared to control cells. The investigation revealed that RUNX2 was an essential factor for the AA mediated induction of MMP-13 and that RUNX2 and BMP2 functionally cooperated to regulate MMP-13 mRNA levels.
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Stephens, Alexandre. "Genetic and Functional Characterization of RUNX2." Thesis, Griffith University, 2007. http://hdl.handle.net/10072/365677.
Full textAbstract:
RUNX2 belongs to the RUNT domain family of transcription factors of which three have been identified in humans (RUNX1, RUNX2 and RUNX3). RUNX proteins are vital for metazoan development and participate in the regulation of cellular differentiation and cell cycle progression (Coffman, 2003). RUNX2 is required for proper bone formation by driving the differentiation of osteoblasts from mesenchymal progenitors during development (Ducy et al, 1997; Komori et al, 1997; Otto et al, 1997). RUNX2 is also vital for chondrocyte maturation by promoting the differentiation of chondrocytes to the hypertrophic phenotype (Enomoto et al, 2000). The consequences of completely disrupting the RUNX2 locus in mice provided compelling and conclusive evidence for the biological importance of RUNX2 where knockout mice died shortly after birth with a complete lack of bone formation (Komori et al, 1997; Otto et al, 1997). A further indication of the requisite role of RUNX2 in skeletal development was the discovery that RUNX2 haploinsufficiency in humans and mice caused the skeletal syndrome Cleidocranial Dysplasia (CCD) (Mundlos et al, 1997; Lee et al, 1997). A unique feature of RUNX2 is the consecutive polyglutamine and polyalanine tracts (Q/A domain). Mutations causing CCD have been observed in the Q/A domain of RUNX2 (Mundlos et al, 1997). The Q/A domain is an essential part of RUNX2 and participates in transactivation function (Thirunavukkarasu et al, 1998). Previous genotyping studies conducted in our laboratory identified several rare RUNX2 Q/A variants in addition to a frequently occurring 18 base pair deletion of the polyalanine tract termed the 11Ala allele. Analysis of serum parameters in 78 Osteoarthritis patients revealed the 11Ala allele was associated with significantly decreased osteocalcin. Furthermore, analysis of 11Ala allele frequencies within a Geelong Osteoporosis Study (GOS) fracture cohort and an appropriate age matched control group revealed the 11Ala allele was significantly overrepresented in fracture cases indicating an association with increased fracture risk. To further investigate the 11Ala allele and rare Q/A variants, 747 DNA samples from the Southeast Queensland bone study were genotyped using PCR and PAGE. The experiment served two purposes: 1) to detect additional rare Q/A variants to enrich the population of already identified mutants and 2) have an independent assessment of the effect of the 11Ala allele on fracture to either support or refute our previous observation which indicated the 11Ala allele was associated with an increased risk of fracture in the GOS. From the 747 samples genotyped, 665 were WT, 76 were heterozygous for the 11Ala allele, 5 were homozygous for the 11Ala allele and 1 was heterozygous for a rare 21 bp deletion of the polyglutamine tract. Chi-square analysis of RUNX2 genotype distributions within fracture and non-fracture groups in the Southeast Queensland bone study revealed that individuals that carried at least one copy of the 11Ala allele were enriched in the fracture group (p = 0.16, OR = 1.712). The OR of 1.712 was of similar magnitude to the OR observed in the GOS case-control investigation (OR = 1.9) providing support for the original study. Monte-Carlo simulations were used to combine the results from the GOS and the Southeast Queensland bone study. The simulations were conducted with 10000 iterations and demonstrated that the maximum probability of obtaining both study results by chance was less than 5 times in two hundred (p < 0.025) suggesting that the 11Ala allele of RUNX2 was associated with an increased fracture risk. The second element of the research involved the analysis of rare RUNX2 Q/A variants identified from multiple epidemiological studies of bone. Q/A repeat variants were derived from four populations: the GOS, an Aberdeen cohort, CAIFOS and a Sydney twin study. Collectively, a total of 20 rare glutamine and one alanine variants were identified from 4361 subjects. All RUNX2 Q/A variants were heterozygous for a mutant allele and a wild type allele. Analysis of incident fracture during a five year follow up period in the CAIFOS revealed that Q-variants (n = 8) were significantly more likely to have fractured compared to non-carriers (p = 0.026, OR 4.932 95% CI 1.2 to 20.1). Bone density data as measured by quantitative ultrasound was available for CAIFOS. Analysis of BUA and SOS Z-scores revealed that Q-repeat variants had significantly lower BUA (p = 0.031, mean Z-score of -0.79) and a trend for lower SOS (p = 0.190, mean Z-score of -0.69). BMD data was available for all four populations. To normalize the data across the four studies, FN BMD data was converted into Z-scores and the effect of the Q/A variants on BMD was analysed using a one sample approach. The analysis revealed Q/A variants had significantly lower FN BMD (p = 0.0003) presenting with a 0.65 SD decrease. Quantitative transactivation analysis was conducted on RUNX2 proteins harbouring rare glutamine mutations and the 11Ala allele. RUNX2 proteins containing a glutamine deletion (16Q), a glutamine insertion (30Q) and the 11Ala allele were overexpressed in NIH3T3 and HEK293 cells and their ability to transactivate a known target promoter was assessed. The 16Q and 30Q had significantly decreased reporter activity compared to WT in NIH3T3 cells (p = 0.002 and 0.016, for 16Q and 30Q, respectively). In contrast 11Ala RUNX2 did not show significantly different promoter activation potential (p = 0.54). Similar results were obtained in HEK293 cells where both the 16Q and 30Q RUNX2 displayed decreased reporter activity (p=0.007 and 0.066 for 16Q and 30Q respectively) whereas the 11Ala allele had no material effect on RUNX2 function (p = 0.20). The RUNX2 gene target reporter assay provided evidence to suggest that variation within the glutamine tract of RUNX2 was capable of altering the ability of RUNX2 to activate a known target promoter. In contrast, the 11Ala allele showed no variation in RUNX2 activity. The third feature of the research served the purpose of identifying potential RUNX2 gene targets with particular emphasis on discovering genes cooperatively regulated by RUNX2 and the powerful bone promoting agent BMP2. The experiment was conducted by creating stably transfected NIH3T3 cells lines overexpressing RUNX2 or BMP2 or both RUNX2 and BMP2. Microarray analysis revealed very few genes were differentially regulated between standard NIH3T3 cells and cells overexpressing RUNX2. The results were confirmed via RT-PCR analysis which demonstrated that the known RUNX2 gene targets Osteocalcin and Matrix Metalloproteinase-13 were modestly induced 2.5 fold (p = 0.00017) and 2.1 fold (p = 0.002) respectively in addition to identifying only two genes (IGF-II and SCYA11) that were differentially regulated greater than 10 fold. IGF-II and SYCA11 were significantly down-regulated 27.6 fold (p = 1.95 x 10-6) and 10.1 fold (p = 0.0002) respectively. The results provided support for the notion that RUNX2 on its own was not sufficient for optimal gene expression and required the presence of additional factors. To discover genes cooperatively regulated by RUNX2 and BMP2, microarray gene expression analysis was performed on standard NIH3T3 cells and NIH3T3 cells stably transfected with both RUNX2 and BMP2. Comparison of the gene expression profiles revealed the presence of a large number of differentially regulated genes. Four genes EHOX, CCL9, CSF2 and OSF-1 were chosen to be further characterized via RT-PCR. Sequential RT-PCR analysis on cDNA derived from control cells and cells stably transfected with either RUNX2, BMP2 or both RUNX2/BMP2 revealed that EHOX and CSF2 were cooperatively induced by RUNX2 and BMP2 whereas CCL9 and OSF-1 were suppressed by BMP2. The overexpression of both RUNX2 and BMP2 in NIH3T3 fibroblasts provided a powerful model upon which to discover potential RUNX2 gene targets and also identify genes synergistically regulated by BMP2 and RUNX2. The fourth element of the research investigated the role of RUNX2 in the ascorbic acid mediated induction of MMP-13 mRNA. The study was carried out using NIH3T3 cell lines stably transfected with BMP2, RUNX2 and both BMP2 and RUNX2. The cell lines were grown to confluence and subsequently cultured for a further 12 days in standard media or in media supplemented with AA. RT-PCR analysis was used to assess MMP-13 mRNA expression. The RT-PCR results demonstrated that AA was not sufficient for inducing MMP-13 mRNA in NIH3T3 cells. In contrast RUNX2 significantly induced MMP-13 levels 85 fold in the absence of AA (p = 0.0055) and upregulated MMP-13 mRNA levels 254 fold in the presence of AA (p = 0.0017). The results demonstrated that RUNX2 was essential for the AA mediated induction of MMP-13 mRNA in NIH3T3 cells. The effect of BMP2 on MMP-13 expression was also investigated. BMP2 induced MMP-13 mRNA transcripts a modest 3.8 fold in the presence of AA (p = 0.0027). When both RUNX2 and BMP2 were overexpressed in the presence of AA, MMP-13 mRNA levels were induced a massive 4026 fold (p = 8.7 x 10-4) compared to control cells. The investigation revealed that RUNX2 was an essential factor for the AA mediated induction of MMP-13 and that RUNX2 and BMP2 functionally cooperated to regulate MMP-13 mRNA levels.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Faculty of Health
Full Text
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Ferguson, Alison Mary. "The Role of RUNX Transcription Factors in Prostate Development and Tumorigenesis." Thesis, The University of Sydney, 2016. http://hdl.handle.net/2123/16898.
Full textAbstract:
Prostate cancer is the most prevalent malignant neoplasia affecting men over 65 years of age. While prostate carcinoma is considered mostly curable when confined to the prostatic capsule, more aggressive forms have a predilection to metastasise to the bone. Increased expression of RUNX2 in primary tumours has been proposed to promote bone metastasis due to its critical role in bone regulation. However a role in tumour development and progression remains to be elucidated for RUNX2, or its β-subunit, CBFb. This thesis examines a role for RUNX2 during prostate cancer progression and defines a novel role for CBFβ and the RUNX-associated transcriptional repressor, ETO in prostate development and tumorigenesis. ETO was differentially expressed during prostate development and tumorigenesis, in vivo. Additionally, in vitro, ETO protein expression was confirmed in all prostate cancer cell subtypes, with high expression associated with aggressive, metastatic prostate cancer cells. Manipulation of ETO in vitro demonstrated a requirement for ETO in the growth and invasion of human prostate cancer cells. Subsequent examination of these cells in subcutaneous xenograft models revealed a requirement for ETO in aggressive tumour growth in vivo. Examination of CBFβ in vivo, demonstrated its differential expression during prostate development and tumorigenesis. CBFβ knockdown in an aggressive prostate cancer cell line demonstrated that CBFβ expression was required for growth and invasion in vitro and delayed tumour growth following in vivo xenograft examination. RUNX2 was shown to promote increased cell growth and invasion in human prostate cancer cells in vitro. Subsequent in vivo examination of a non-aggressive prostate cancer cell line following forced RUNX2 expression demonstrated decreased primary tumour growth but was associated with increased metastasis. These data provide a new role for ETO and CBFβ in prostate development and tumorigenesis and a novel role for RUNX2 in the phenotypic shift associated with metastatic prostate cancer.
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Ferrari, Nicola. "Investigating RUNX transcription factors in mammary gland development and breast cancer." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4790/.
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Breast cancer is the third most common cause of cancer death in the UK, accountable for more than 11000 deaths in 2010 alone (www.cancerresearchuk. org). Developmental pathways commonly required for normal development are often hijacked during tumour progression, so a better understanding of mammary gland development is necessary to fully understand the roots of breast cancer. The Runx gene family are known to be important regulators of development in different lineages. In particular RUNX1 and RUNX2 have been widely studied in the context of haematopoiesis and osteogenesis respectively, but their role in epithelial tissue is much less well understood. In this thesis a role for RUNX1 and RUNX2 in mammary development and breast cancer has been identified. The first part of this study is focused on characterizing the expression and function of the Runx genes in the mammary epithelium. RUNX1 and RUNX2 protein levels fluctuate during embryonic and adult mammary development, and an in vivo conditional knockout strategy shows that both genes are important for maintenance of mammary epithelium homeostasis. Moreover, combined loss of RUNX1 and RUNX2 significantly perturbs the normal mammary architecture with an expansion of the basal population in vivo and the appearance of preneoplastic lesions in aged mammary glands. An exciting new role for RUNX2 in mammary stem cells has also been revealed showing that RUNX2 is important for the regenerative potential of mammary epithelial cells in vitro. Evidence is also presented to indicate that RUNX2 could be linked to regulation of quiescence and Wnt signalling in the stem cell compartment and during transformation. Finally, the role of these genes in breast cancer is discussed demonstrating involvement of RUNX1 and RUNX2 specifically in the triple negative (ER-PR-HER2-) subtype. In particular, for the first time, RUNX1 is revealed as an independent prognostic indicator correlating with poor prognosis in triple negative tumours. Meanwhile, evidence from various mouse models demonstrates that RUNX2 may be specifically involved in the squamous metaplastic form of this disease.
Books on the topic "RUNX"
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Groner, Yoram, Yoshiaki Ito, Paul Liu, James C. Neil, Nancy A. Speck, and Andre van Wijnen, eds. RUNX Proteins in Development and Cancer. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2.
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Sammy Sosa: Home-run hitter = bateador de home runs. New York: Rosen Pub. Group's PowerKids Press & Buenas Letras, 2001.
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Club, Colorado Mountain, ed. Run the Rockies: Classic trail runs in Colorado's Front Range. Golden, Colo: Colorado Mountain Club Press, 2004.
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When the rivers run dry: What happens when our water runs out? London: Eden Project, 2007.
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How to run: [from fun runs to marathons and everything in between. London: Simon & Schuster Illustrated, 2011.
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Pearce, Fred. When the rivers run dry: What happens when our water runs out? London: Eden Project, 2006.
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Run, run, run away. Oregon?]: [publisher not identified], 2015.
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Chukhov, Petŭr. Runi. [Bulgaria?]: Ab Izdatelsko Atelie, 1998.
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Griffiths, Niall. Runt. London: Jonathan Cape, 2007.
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Runa. New York, N.Y: Atheneum, 1993.
Find full textBook chapters on the topic "RUNX"
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Ito, Yoshiaki. "RUNX." In Encyclopedia of Signaling Molecules, 4773–81. Cham: Springer International Publishing, 2018. http://dx.doi.org/10.1007/978-3-319-67199-4_101825.
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Ito, Yoshiaki. "RUNX." In Encyclopedia of Signaling Molecules, 1–9. New York, NY: Springer New York, 2017. http://dx.doi.org/10.1007/978-1-4614-6438-9_101825-1.
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Hughes, S., and A. Woollard. "RUNX in Invertebrates." In Advances in Experimental Medicine and Biology, 3–18. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_1.
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Chuang, Linda Shyue Huey, Kosei Ito, and Yoshiaki Ito. "Roles of RUNX in Solid Tumors." In Advances in Experimental Medicine and Biology, 299–320. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_19.
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West, Michelle J., and Paul J. Farrell. "Roles of RUNX in B Cell Immortalisation." In Advances in Experimental Medicine and Biology, 283–98. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_18.
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Passaniti, Antonino, Jessica L. Brusgard, Yiting Qiao, Marius Sudol, and Megan Finch-Edmondson. "Roles of RUNX in Hippo Pathway Signaling." In Advances in Experimental Medicine and Biology, 435–48. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_26.
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Ebihara, Takashi, Wooseok Seo, and Ichiro Taniuchi. "Roles of RUNX Complexes in Immune Cell Development." In Advances in Experimental Medicine and Biology, 395–413. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_24.
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Blumenthal, Ezra, Sarah Greenblatt, Guang Huang, Koji Ando, Ye Xu, and Stephen D. Nimer. "Covalent Modifications of RUNX Proteins: Structure Affects Function." In Advances in Experimental Medicine and Biology, 33–44. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_3.
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Wang, Jae Woong, and Stefano Stifani. "Roles of Runx Genes in Nervous System Development." In Advances in Experimental Medicine and Biology, 103–16. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_8.
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Wang, Chelsia Qiuxia, Michelle Meng Huang Mok, Tomomasa Yokomizo, Vinay Tergaonkar, and Motomi Osato. "Runx Family Genes in Tissue Stem Cell Dynamics." In Advances in Experimental Medicine and Biology, 117–38. Singapore: Springer Singapore, 2017. http://dx.doi.org/10.1007/978-981-10-3233-2_9.
Full textConference papers on the topic "RUNX"
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Chu, Jinn P., and C. H. Lin. "High Performance Cu Containing Ru or RuNx for Barrierless Metallization." In 2008 International Interconnect Technology Conference - IITC. IEEE, 2008. http://dx.doi.org/10.1109/iitc.2008.4546914.
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Yong, T., S. Meyers, N. Davis, and A. Sun. "Involvement of notch and RUNX pathways in human breast cancer." In CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts. American Association for Cancer Research, 2009. http://dx.doi.org/10.1158/0008-5472.sabcs-6021.
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Felcher, Carla M., Johanna M. Tocci, Martin E. Garcia Sola, John H. Bushweller, Lucio H. Castilla, and Edith C. Kordon. "Abstract 5041: Inhibition of RUNX-CBFβ binding reduces RSPO3 expression and EMT features in breast cancer cells." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-5041.
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Matsuo, Junichi, Naing Naing Mon, Akihiro Yamamura, Dede L. Heng, Linda SH Chuang, Motomi Osato, and Yoshiaki Ito. "Abstract 5110: Runx knockout in breast luminal stem/progenitor cells induced precancerous lesion via robust expression of ERα." In Proceedings: AACR Annual Meeting 2018; April 14-18, 2018; Chicago, IL. American Association for Cancer Research, 2018. http://dx.doi.org/10.1158/1538-7445.am2018-5110.
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Sasaski, Asami, Youhei Yanagida, Hiroshi Sugiyama, Souichi Adachhi, and Yasuhiko Kamikubo. "Abstract 2937: The regulation of FGFR signaling by RTK adaptor protein down-regulation through CROX (cluster regulation of RUNX) theory in DNPC." In Proceedings: AACR Annual Meeting 2020; April 27-28, 2020 and June 22-24, 2020; Philadelphia, PA. American Association for Cancer Research, 2020. http://dx.doi.org/10.1158/1538-7445.am2020-2937.
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Battula, Venkata Lokesh, Phuong M. Le, Jeff Sun, Christopher B. Benton, Teresa Mc.Queen, Elizabeth J. Shpall, Carlos E. Bueso-Ramos, Marina Konopleva, and Michael Andreeff. "Abstract 5085: Acute myeloid leukemia cells induce osteogenic differentiation in mesenchymal stem cells through bone morphogenetic protein- and RUNX-2- mediated signaling." In Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA. American Association for Cancer Research, 2015. http://dx.doi.org/10.1158/1538-7445.am2015-5085.
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Pérez-García, S., I. Gutiérrez-Cañas, R. Villanueva-Romero, J. Leceta, J. Fernández, I. González-Άlvaro, Y. Juarranz, and RP Gomariz. "FRI0016 Involvement of runx-2 and β-catenin signaling in the production of adamts-7 and adamts-12 in osteoarthritic synovial fibroblasts." In Annual European Congress of Rheumatology, 14–17 June, 2017. BMJ Publishing Group Ltd and European League Against Rheumatism, 2017. http://dx.doi.org/10.1136/annrheumdis-2017-eular.5808.
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Cobb, Michael G., Dana M. Austin, Dapeng Xu, and Antonio T. Baines. "Abstract B56: The role of Pim kinases and RUNX transcription factors as potential molecular targets of K-Ras signaling in pancreatic cancer cells." In Abstracts: AACR Special Conference on Pancreatic Cancer: Progress and Challenges; June 18-21, 2012; Lake Tahoe, NV. American Association for Cancer Research, 2012. http://dx.doi.org/10.1158/1538-7445.panca2012-b56.
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Okoli, Uzoamaka A. "Abstract PO-150: Comparison of RUNX1, RUNX2, RUNX3 and CBFβ gene expression in breast tumors Indicate ethnic differences and similarities by receptor status." In Abstracts: AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; October 6-8, 2021. American Association for Cancer Research, 2022. http://dx.doi.org/10.1158/1538-7755.disp21-po-150.
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La Rosa, Alessandro. "ATLAS Pixel Detector: Operational Experience and Run1$\rightarrow$Run2 Transition." In The 23rd International Workshop on Vertex Detectors. Trieste, Italy: Sissa Medialab, 2015. http://dx.doi.org/10.22323/1.227.0001.
Full textReports on the topic "RUNX"
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Zhang S. Y. and V. Ptitsyn. Proton Beam Emittance Growth in Run5 and Run6. Office of Scientific and Technical Information (OSTI), November 2006. http://dx.doi.org/10.2172/1061848.
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Zhang S. Y. and D. Trbojevic. Observation of Experimental Background in Proton Run5 and Run6. Office of Scientific and Technical Information (OSTI), November 2006. http://dx.doi.org/10.2172/1061849.
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Donaldson, Jason, and Giorgia Piacentino. Money Runs. Cambridge, MA: National Bureau of Economic Research, September 2019. http://dx.doi.org/10.3386/w26298.
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Andolfatto, David, Ed Nosal, and Bruno Sultanum. Preventing Bank Runs. Federal Reserve Bank of St. Louis, 2014. http://dx.doi.org/10.20955/wp.2014.021.
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Andolfatto, David, and Ed Nosal. Shadow Bank Runs. Federal Reserve Bank of St. Louis, 2020. http://dx.doi.org/10.20955/wp.2020.012.
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Bernardo, Antonio, and Ivo Welch. Financial Market Runs. Cambridge, MA: National Bureau of Economic Research, October 2002. http://dx.doi.org/10.3386/w9251.
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He, Zhiguo, and Wei Xiong. Dynamic Debt Runs. Cambridge, MA: National Bureau of Economic Research, November 2009. http://dx.doi.org/10.3386/w15482.
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Gutiérrez, José E., and Luis Fernández Lafuerza. Credit line runs and bank risk management: evidence from the disclosure of stress test results. Madrid: Banco de España, December 2022. http://dx.doi.org/10.53479/25006.
Full textAbstract:
As noted in recent literature, firms can run on credit lines due to fear of future credit restrictions. We exploit the 2011 stress test supervised by the European Banking Authority (EBA) and the Spanish Central Credit Register to explore: 1) the occurrence and magnitude of these runs after the release of negative stress test results; and 2) banks’ behaviour before and after the release of this information. We find that, following the release of the results, firms drew down approximately 10 pp more available funds from lines granted by banks that had a worse performance in the stress test. Moreover, before the release date, poorer performing banks were more likely to reduce the size of credit lines, while those with more significant balances of undrawn credit lines were more likely to cut term lending.
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Gutiérrez, José E., and Luis Fernández Lafuerza. Credit line runs and bank risk management: evidence from the disclosure of stress test results. Madrid: Banco de España, January 2023. http://dx.doi.org/10.53479/24998.
Full textAbstract:
As noted in recent literature, firms can run on credit lines due to fear of future credit restrictions. We exploit the 2011 stress test supervised by the European Banking Authority (EBA) and the Spanish Central Credit Register to explore: 1) the occurrence and magnitude of these runs after the release of negative stress test results; and 2) banks’ behaviour before and after the release of this information. We find that, following the release of the results, firms drew down approximately 10 pp more available funds from lines granted by banks that had a worse performance in the stress test. Moreover, before the release date, poorer performing banks were more likely to reduce the size of credit lines, while those with more significant balances of undrawn credit lines were more likely to cut term lending.
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Rode, C. A1 cryogenic magnet runs. Office of Scientific and Technical Information (OSTI), July 1994. http://dx.doi.org/10.2172/1155894.
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