The Experts below are selected from a list of 16575 Experts worldwide ranked by ideXlab platform
Sharmila Shankar - One of the best experts on this subject based on the ideXlab platform.
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inhibition of pi3k akt and mapk erk pathways causes activation of foxo transcription factor leading to cell cycle arrest and apoptosis in pancreatic cancer
Journal of Molecular Signaling, 2010Co-Authors: Rakesh K Srivastava, Sharmila ShankarAbstract:Background Mammalian forkhead members of the class O (FOXO) transcription factors, including FOXO1, FOXO3a, and FOXO4, are implicated in the regulation of several biological processes, including the stress resistance, metabolism, cell cycle, apoptosis and DNA repair. The objectives of this study were to examine the molecular mechanisms by which FOXO transcription factors induced cell cycle arrest and apoptosis and enhanced anti-proliferative effects of sulforaphane (SFN, an active compound in cruciferous vegetables) in pancreatic cancer cells.
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inhibition of pi3k akt and mapk erk pathways causes activation of foxo transcription factor leading to cell cycle arrest and apoptosis in pancreatic cancer
Journal of Molecular Signaling, 2010Co-Authors: Sanjit K Roy, Rakesh K Srivastava, Sharmila ShankarAbstract:Mammalian forkhead members of the class O (FOXO) transcription factors, including FOXO1, FOXO3a, and FOXO4, are implicated in the regulation of several biological processes, including the stress resistance, metabolism, cell cycle, apoptosis and DNA repair. The objectives of this study were to examine the molecular mechanisms by which FOXO transcription factors induced cell cycle arrest and apoptosis and enhanced anti-proliferative effects of sulforaphane (SFN, an active compound in cruciferous vegetables) in pancreatic cancer cells. Our data demonstrated that SFN inhibited cell proliferation and colony formation, and induced apoptosis through caspase-3 activation in pancreatic cancer cells. The inhibition of PI3K/AKT and MEK/ERK pathways activated FOXO transcription factors. SFN inhibited phosphorylation of AKT and ERK, and activated FOXO transcription factors, leading to cell cycle arrest and apoptosis. Phosphorylation deficient mutants of FOXO proteins enhanced FOXO transcriptional activity, and further enhanced SFN-induced FOXO activity and apoptosis. SFN induced the expression of p21/CIP1 and p27/KIP1, and inhibited the expression of cyclin D1. These data suggest that inhibition of PI3K/AKT and ERK pathways acts together to activate FOXO transcription factor and enhances SFN-induced FOXO transcriptional activity, leading to cell cycle arrest and apoptosis.
Irwin H Gelman - One of the best experts on this subject based on the ideXlab platform.
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a genome wide rnai screen identifies foxo4 as a metastasis suppressor through counteracting pi3k akt signal pathway in prostate cancer
PLOS ONE, 2014Co-Authors: Lingqiu Gao, Catherine Baranowski, Bryan Gillard, Jianmin Wang, Ryan Ransom, Irwin H GelmanAbstract:Activation of the PI3K/AKT signal pathway is a known driving force for the progression to castration-recurrent prostate cancer (CR-CaP), which constitutes the major lethal phenotype of CaP. Here, we identify using a genomic shRNA screen the PI3K/AKT-inactivating downstream target, FOXO4, as a potential CaP metastasis suppressor. FOXO4 protein levels inversely correlate with the invasive potential of a panel of human CaP cell lines, with decreased mRNA levels correlating with increased incidence of clinical metastasis. Knockdown (KD) of FOXO4 in human LNCaP cells causes increased invasion in vitro and lymph node (LN) metastasis in vivo without affecting indices of proliferation or apoptosis. Increased Matrigel invasiveness was found by KD of FOXO1 but not FOXO3. Comparison of differentially expressed genes affected by FOXO4-KD in LNCaP cells in culture, in primary tumors and in LN metastases identified a panel of upregulated genes, including PIP, CAMK2N1, PLA2G16 and PGC, which, if knocked down by siRNA, could decrease the increased invasiveness associated with FOXO4 deficiency. Although only some of these genes encode FOXO promoter binding sites, they are all RUNX2-inducible, and RUNX2 binding to the PIP promoter is increased in FOXO4-KD cells. Indeed, the forced expression of FOXO4 reversed the increased invasiveness of LNCaP/shFOXO4 cells; the forced expression of FOXO4 did not alter RUNX2 protein levels, yet it decreased RUNX2 binding to the PIP promoter, resulting in PIP downregulation. Finally, there was a correlation between FOXO4, but not FOXO1 or FOXO3, downregulation and decreased metastasis-free survival in human CaP patients. Our data strongly suggest that increased PI3K/AKT-mediated metastatic invasiveness in CaP is associated with FOXO4 loss, and that mechanisms to induce FOXO4 re-expression might suppress CaP metastatic aggressiveness.
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abstract 1449 a loss of function shrna library screen for the cell invasion suppressing genes in lncap prostate cancer cells
Cancer Research, 2011Co-Authors: Catherine Baranowski, Irwin H GelmanAbstract:Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Metastasis remains the primary cause of cancer-related death. Metastasis reduces the 5-year survival rate dramatically, as observed in prostate cancer, and yet, little is known about the genes that control the metastatic process. shRNA libraries are emerging as powerful tools for the identification of genes with specific functions. Here, we describe the successful application of this functional gene-discovery system by identifying genes suppressing tumor invasion, a process that is essential for metastasis. After infecting human prostate cancer cells, LNCaP, with Decode lentiviruses encoding the entire human genomic shRNA library, highly invasive variants were selected using Matrigel invasion assays. After three cycles of selection, we isolated highly invasive clones from 7 shRNA library pools. Using DNA sequence analysis and a database search, we identified five genes previously not associated with control of tumor cell invasiveness: forkhead box O4 (FOXO4), kinesin family member 3B (KIF 3B), signal transducing adaptor molecule (SH3 domain and ITAM motif) 1 (STAM), SUMO1/sentrin specific peptidase 1 (SENP1), and Homo sapiens solute carrier family 17 (SLC17A4). Silencing of FOXO4, a member of Forkhead transcription factors family, by small interfering RNAs indeed increased invasion of LNCaP cells. Reintroducing FOXO4 decreased invasion in the highly invasive prostate cancer cell lines DU145 and CWR22v1. In order to show that increased invasiveness was not a result of a change in survival ability, apoptosis and proliferation were assessed. The results indicate that FOXO4 did not affect proliferation and apoptosis in LNCaP cells. In mammals, the FOXO family comprises four members (FOXO1, FOXO3, FOXO4 and FOXO6). Though FOXO1, 3 and 4 have previously been described as having redundant functions, it appears that FOXO4 has unique metastasis suppressor function in prostate cancer. Additionally, an analysis of web-based gene expression databanks indicates that FOXO4 typically is downregulated in metastatic lesions of breast, prostate and colon cancers when compared to primary lesions. Further characterization of these candidate genes would clarify the complex mechanisms of invasion and metastasis and might reveal new classes of therapeutic targets distinct from known metastatic genes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1449. doi:10.1158/1538-7445.AM2011-1449
Dana T. Graves - One of the best experts on this subject based on the ideXlab platform.
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the role of forkhead box 1 foxo1 in the immune system dendritic cells t cells b cells and hematopoietic stem cells
Critical Reviews in Immunology, 2017Co-Authors: Adriana Alicia Cabreraortega, Daniel Feinberg, Youde Liang, Carlos Rossa, Dana T. GravesAbstract:Forkhead box-O (FOXO) transcription factors have a fundamental role in the development and differentiation of immune cells. FOXO1 and FOXO3 are FOXO members that are structurally similar and bind to the same conserved consensus DNA sequences to induce transcription. FOXO1 has been studied in detail in the activation of dendritic cells (DCs), where it plays an important role through the regulation of target genes such as ICAM-1, CCR7, and the integrin αvβ3. FOXO1 is activated by bacteria challenge in DCs and promotes DC bacterial phagocytosis, migration, homing to lymph nodes, DC stimulation of CD4+ T cells and resting B cells, and antibody production. Deletion of FOXO1 in DCs enhances susceptibility to bacteria-induced periodontal disease. FOXO1 and FOXO3 maintain naive T cell quiescence and survival. FOXO1 and FOXO3 enhance the formation of regulatory T cells and inhibit the formation of T-helper 1 (Th1) and Th17 cells. FOXO1 promotes differentiation, proliferation, survival, immunoglobulin gene rearrangement, and class switching in B cells, but FOXO3 has little effect. Both FOXO1 and FOXO3 are important in the maintenance of hematopoietic stem cells by protecting them from oxidative stress. This review examines FOXO1/FOXO3 in the adaptive immune response, key target genes, and FOXO inhibition by the phosphoinositide 3-kinase/AKT pathway.
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Role of Forkhead Transcription Factors in Diabetes-Induced Oxidative Stress
Experimental diabetes research, 2012Co-Authors: Bhaskar Ponugoti, Guangyu Dong, Dana T. GravesAbstract:Diabetes is a chronic metabolic disorder, characterized by hyperglycemia resulting from insulin deficiency and/or insulin resistance. Recent evidence suggests that high levels of reactive oxygen species (ROS) and subsequent oxidative stress are key contributors in the development of diabetic complications. The FOXO family of forkhead transcription factors including FOXO1, FOXO3, FOXO4, and FOXO6 play important roles in the regulation of many cellular and biological processes and are critical regulators of cellular oxidative stress response pathways. FOXO1 transcription factors can affect a number of different tissues including liver, retina, bone, and cell types ranging from hepatocytes to microvascular endothelial cells and pericytes to osteoblasts. They are induced by oxidative stress and contribute to ROS-induced cell damage and apoptosis. In this paper, we discuss the role of FOXO transcription factors in mediating oxidative stress-induced cellular response.
Zuzana Tothova - One of the best experts on this subject based on the ideXlab platform.
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p16ink4a is a key downstream mediator of the deleterious effects of foxo deficiency on maintenance of the hematopoietic stem cell compartment
Blood, 2008Co-Authors: Zuzana Tothova, James W Horner, Stephen M Sykes, Dena S Leeman, Norman E Sharpless, Gary D GillilandAbstract:Regulation of oxidative stress in the hematopoietic stem cell (HSC) compartment is critical for the maintenance of HSC self-renewal. A number of reports have previously implicated p16 in aging of HSCs, pancreatic β-islet cells and subventricular zone progenitors in the brain [1–3]. In the context of the hematopoietic system, p16 INK4a expression in HSCs increases with age, and correlates with decreased HSC repopulating ability, decreased self-renewal, and increased apoptosis with stress [1]. We and others have recently reported that FoxO play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment [4, 5]. Young mice deficient in FoxO1 , FOXO3 , and FoxO4 in the adult hematopoietic system, with striking similarity to aging wild-type mice, show a defect in bone marrow repopulating ability, decrease in self-renewal, myeloid skewing in differentiation and increased levels of apoptosis. Furthermore, young FoxO -deficient HSC show increased levels of p16 when compared to their wildtype counterparts. These collective findings suggested the possibility that FoxO loss could result in accelerated aging of HSC due to increased expression of p16 as a consequence of increased ROS. To test the hypothesis that p16 is one of the key mediators of FoxO loss responsible for accelerated aging of HSC, we deleted FoxO1 , FOXO3 , and FoxO4 in the adult hematopoietic system of mice deficient in p16 INK4a . Young mice deficient in FoxO and p16 shared the same characteristics of their HSC(Lin − Sca1 + c-kit + ) compartment as mice deficient in FoxO only, including decreased number of HSC, increased percentage of HSC entering S/G2/M and apoptosis, and increased levels of ROS as compared to their wildtype counterparts. However, in a setting of long-term repopulation studies, bone marrow isolated from mice deficient in p16 and FoxO demonstrated a rescue of long-term repopulation for up to 20 weeks, as compared to FoxO deficient bone marrow that showed a severe defect in long-term repopulation. p16 deficiency in the setting of FoxO deficiency did not result in reduction of ROS levels in the HSC compartment. Taken together, these findings indicate that p16 is a critical downstream mediator of FoxO in the maintenance of the HSC compartment, and that it can dissociate the detrimental effects of ROS on HSC self-renewal in a setting of FoxO deficiency.
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foxos are lineage restricted redundant tumor suppressors and regulate endothelial cell homeostasis
Cell, 2007Co-Authors: Ramya Kollipara, Hongkai Ji, Yonghong Xiao, Zhihu Ding, Lili Miao, Zuzana Tothova, James W Horner, Daniel R Carrasco, Shan JiangAbstract:Activated phosphoinositide 3-kinase (PI3K)-AKT signaling appears to be an obligate event in the development of cancer. The highly related members of the mammalian FoxO transcription factor family, FoxO1, FOXO3, and FoxO4, represent one of several effector arms of PI3K-AKT signaling, prompting genetic analysis of the role of FoxOs in the neoplastic phenotypes linked to PI3K-AKT activation. While germline or somatic deletion of up to five FoxO alleles produced remarkably modest neoplastic phenotypes, broad somatic deletion of all FoxOs engendered a progressive cancer-prone condition characterized by thymic lymphomas and hemangiomas, demonstrating that the mammalian FoxOs are indeed bona fide tumor suppressors. Transcriptome and promoter analyses of differentially affected endothelium identified direct FoxO targets and revealed that FoxO regulation of these targets in vivo is highly context-specific, even in the same cell type. Functional studies validated Sprouty2 and PBX1, among others, as FoxO-regulated mediators of endothelial cell morphogenesis and vascular homeostasis.
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foxos are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress
Cell, 2007Co-Authors: Diego H Castrillon, Ramya Kollipara, Zuzana Tothova, Brian J P Huntly, Dana E Cullen, Elizabeth P Mcdowell, Suzan LazokallanianAbstract:Summary To understand the role of FoxO family members in hematopoiesis, we conditionally deleted FoxO1 , FOXO3 , and FoxO4 in the adult hematopoietic system. FoxO- deficient mice exhibited myeloid lineage expansion, lymphoid developmental abnormalities, and a marked decrease of the lineage-negative Sca-1 + , c-Kit + (LSK) compartment that contains the short- and long-term hematopoietic stem cell (HSC) populations. FoxO -deficient bone marrow had defective long-term repopulating activity that correlated with increased cell cycling and apoptosis of HSC. Notably, there was a marked context-dependent increase in reactive oxygen species (ROS) in FoxO -deficient HSC compared with wild-type HSC that correlated with changes in expression of genes that regulate ROS. Furthermore, in vivo treatment with the antioxidative agent N-acetyl-L-cysteine resulted in reversion of the FoxO -deficient HSC phenotype. Thus, FoxO proteins play essential roles in the response to physiologic oxidative stress and thereby mediate quiescence and enhanced survival in the HSC compartment, a function that is required for its long-term regenerative potential.
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the role of forkhead transcription factors foxo1 FOXO3 and foxo4 in hematopoiesis and leukemogenesis
Blood, 2005Co-Authors: Ramya Kollipara, Zuzana Tothova, Gary D GillilandAbstract:Abstract FoxO is a family of forkhead transcription factors that negatively regulate proliferation and survival signals in hematopoietic cells. We and others have previously shown that inhibition of the three members of this family (FoxO1, FOXO3 and FoxO4) by leukemogenic tyrosine kinase fusion genes results in enhanced proliferative and survival signaling in leukemic cells. For example, the transforming activities of the lymphoma associated NPM-ALK (nucleophosmin-anaplastic lymphoma kinase) fusion, BCR-ABL, or FLT3-ITD, are mediated in part by inactivation of FoxO through phosphorylation and ubiquitin mediated degradation by constitutively active Akt (Gu TL, et al. Blood 2004), with subsequent induction of proliferative and survival signals. Furthermore, inhibition of FoxO is required for efficient transformation of hematopoietic cells. However, the roles of FoxO in adult hematopoiesis are unknown. We have initiated studies to examine the role of FoxO in the context of normal hematopoiesis and leukemogenesis using a triple conditional knockout mouse for each of the FoxO1, FOXO3 and FoxO4 alleles. The FoxO alleles are flanked by lox-P sites and conditional excision is mediated by Cre expression under the control of the interferon inducible Mx1 promoter. Based on the normal function of FoxO family members to repress proliferative and survival signals, we hypothesized that the deletion of FoxO subfamily members would lead to an enhanced proliferation and survival in the hematopoietic compartment, and might contribute to the development of a myeloproliferative and/or lymphoproliferative phenotype in vivo. Triple homozygous conditional FoxO knockout mice were generated in an Mx1-Cre background to allow for excision of the FoxO alleles in the hematopoietic stem cell compartment after treatment with pIpC. Complete excision of each of the three alleles in the hematopoietic compartment was confirmed. However, in contrast with our working hypothesis, we observed that loss of function of FoxO family members was associated with a relatively subtle hematopoietic phenotype with 12 months of follow-up. The phenotype includes a non-fatal mild myeloproliferative phenotype that is progressive over time and characterized by modest splenomegaly, extramedullary hematopoiesis and increased mature myeloid populations in bone marrow and spleen. In addition, there are subtle alterations in both B and T lymphoid cell populations, including a decrease in both immature and mature B cells in the spleen and bone marrow; and abnormalities of CD4+CD8+ double positive and CD4+ and CD8+ T cells in the thymus. Examination of stem and progenitor populations also revealed subtle differences in the HSC and CLP progenitor populations at 4 weeks post pIpC. Thus, these data indicate that complete loss of FoxO function in the adult hematopoietic compartment results in a relatively subtle hematopoietic phenotype. They further demonstrate that although inhibition of FoxO family members is required for efficient transformation of hematopoietic cells by leukemogenic fusion tyrosine kinases, loss of FoxO function alone is not sufficient to induce a leukemic phenotype.
Mien Chie Hung - One of the best experts on this subject based on the ideXlab platform.
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deciphering the role of forkhead transcription factors in cancer therapy
Current Drug Targets, 2011Co-Authors: Jer Yen Yang, Mien Chie HungAbstract:Forkhead O transcription factors (FOXO) are critical for the regulation of cell cycle arrest, cell death, and DNA damage repair. Inactivation of FOXO proteins may be associated with tumorigenesis, including breast cancer, prostate cancer, glioblastoma, rhabdomyosarcoma, and leukemia. Accumulated evidence shows that activation of oncogenic pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase suppresses FOXO transcriptional activity through the phosphorylation of FOXOs at different sites that ultimately leads to nuclear exclusion and degradation of FOXOs. In addition, posttranslational modifications of FOXOs such as acetylation, methylation and ubiquitination also contribute to modulating FOXO3a functions. Several anti-cancer drugs like paclitaxel, imatinib, and doxorubicin activate FOXO3a by counteracting those oncogenic pathways which restrain FOXOs functions. In this review, we will illustrate the regulation of FOXOs and reveal potential therapeutics that target FOXOs for cancer treatment.
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a new fork for clinical application targeting forkhead transcription factors in cancer
Clinical Cancer Research, 2009Co-Authors: Jer Yen Yang, Mien Chie HungAbstract:Forkhead O transcription factors (FOXO) play a pivotal role in the regulation of a myriad of cellular functions including cell cycle arrest, cell death, and protection from stress stimuli. Activation of cell survival pathways such as phosphoinositide-3-kinase/AKT/IKK or RAS/mitogen-activated protein kinase are known to phosphorylate FOXOs at different sites which cause FOXOs nuclear exclusion and degradation, resulting in the suppression of FOXO's transcriptional activity. Perturbation of FOXO's function leads to deregulated cell proliferation and accumulation of DNA damage, resulting in diseases such as cancer. Emerging evidence shows that active FOXO proteins are crucial for keeping cells in check; and inactivation of FOXO proteins is associated with tumorigenesis, including breast cancer, prostate cancer, glioblastoma, rhabdomyosarcoma, and leukemia. Moreover, clinically used drugs like paclitaxel, imatinib, and doxorubicin have been shown to achieve their therapeutic effects through activation of FOXO3a and FOXO3a targets. In this review, we will focus the novel functions of FOXOs revealed in recent studies and further highlight FOXOs as new therapeutic targets in a broad spectrum of cancers.
