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Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of SOCS5 in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here we report that SOCS5 expression is epigenetically regulated by DNMT3A-mediated DNA methylation and MeCP2-mediated histone deacetylation. We demonstrate that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death in vitro. Mechanistically, SOCS5 silencing induces activation of Janus kinase signal transducers and activators of transcription signaling, and negatively regulates IL7 and IL4 receptors. Using a human T-ALL murine xenograft model, we demonstrate that genetic inactivation of SOCS5 accelerates leukemia engraftment, progression and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL. This article is protected by copyright. All rights reserved.
This article was published in the following journal.
Name: Cancer science
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Janus kinases (JAKs) and their downstream STAT proteins play key roles in cytokine signaling, tissue homeostasis, and cancer development. Using a breast cancer model that conditionally lacks Janus kin...
JAK/STAT is an intracellular signaling pathway, which plays a key role in downstream transmission of extracellular signals from cell membrane to the cell nucleus. This pathway is activated by cytokine...
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Epigenetic silencing of genes enhanced by collective role of reactive oxygen species and MAPK signaling downstream ERK/Snail axis: Ectopic application of hydrogen peroxide repress CDH1 gene by enhanced DNA methyltransferase activity in human breast cancer.
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This study will investigate whether inhibitors of the JAK / STAT signaling pathway can increase anti-inflammatory functions of B cells in patients with RA using in vitro and in vivo experi...
The current standard for recurrent, persistent or metastatic cervical cancer is palliative chemotherapy with cisplatin topotecan, however, the results need to be improved. Epigenetic aberr...
Based on preclinical data implicating GR, AR, and JAK/STAT activation as potent mechanisms of breast cancer cell survival despite chemotherapy administration (i.e. chemotherapy resistance)...
This phase I trial studies the side effects and best dose of STAT inhibitor OPB-111077 when given together with decitabine in treating patients with acute myeloid leukemia that does not re...
It is a well known fact that the JAK-STAT pathway plays a pivotal role in the pathogenesis of alopecia areata. Both phosphorylated STAT 1 and 3 have been found to be upregulated in the dis...
A family of transcription factors containing SH2 DOMAINS that are involved in CYTOKINE-mediated SIGNAL TRANSDUCTION. STAT transcription factors are recruited to the cytoplasmic region of CELL SURFACE RECEPTORS and are activated via PHOSPHORYLATION. Once activated they dimerize and translocate into the CELL NUCLEUS where they influence GENE expression. They play a role in regulating CELL GROWTH PROCESSES and CELL DIFFERENTIATION. STAT transcription factors are inhibited by SUPPRESSOR OF CYTOKINE SIGNALING PROTEINS and PROTEIN INHIBITORS OF ACTIVATED STAT.
A family of intracellular tyrosine kinases that participate in the signaling cascade of cytokines by associating with specific CYTOKINE RECEPTORS. They act upon STAT TRANSCRIPTION FACTORS in signaling pathway referred to as the JAK/STAT pathway. The name Janus kinase refers to the fact the proteins have two phosphate-transferring domains.
A family of proteins that play a role in CHROMATIN REMODELING. They are best known for silencing HOX GENES and the regulation of EPIGENETIC PROCESSES.
Cell regulatory signaling system that controls progression through S PHASE and stabilizes the replication forks during conditions that could affect the fidelity of DNA REPLICATION, such as DNA DAMAGE or depletion of nucleotide pools.
The cellular signaling system that halts the progression of cells through MITOSIS or MEIOSIS if a defect that will affect CHROMOSOME SEGREGATION is detected.
The development and maintenance of an organism is orchestrated by a set of chemical reactions that switch parts of the genome off and on at strategic times and locations. Epigenetics is the study of these reactions and the factors that influence them. ...