• Journal of Cancer Prevention
• /
• 제23권4호
• /
• pp.162-169
• /
• 2018

$TGF-{\beta}$ signaling plays a tumor suppressive role in normal and premalignant cells but promotes tumor progression during the late stages of tumor development. The $TGF-{\beta}$ signaling pathway is tightly regulated at various levels, including transcriptional and post-translational mechanisms. Ubiquitination of signaling components, such as receptors and Smad proteins is one of the key regulatory mechanisms of $TGF-{\beta}$ signaling. Tripartite motif (TRIM) family of proteins is a highly conserved group of E3 ubiquitin ligase proteins that have been implicated in a variety of cellular functions, including cell growth, differentiation, immune response, and carcinogenesis. Recent emerging studies have shown that some TRIM family proteins function as important regulators in tumor initiation and progression. This review summarizes current knowledge of TRIM family proteins regulating the $TGF-{\beta}$ signaling pathway with relevance to cancer.

• Journal of Microbiology and Biotechnology
• /
• 제32권1호
• /
• pp.126-140
• /
• 2022

Stem cells can be applied usefully in basic research and clinical field due to their differentiation and self-renewal capacity. The aim of this study was to establish an effective novel therapeutic cellular source and create its molecular expression profile map to elucidate the possible therapeutic mechanism and signaling pathway. We successfully obtained a mesenchymal stem cell population from human embryonic stem cells (hESCs) cultured on chemically defined feeder-free conditions and treated with connective tissue growth factor (CTGF) and performed the expressive proteomic approach to elucidate the molecular basis. We further selected 12 differentially expressed proteins in CTGF-induced hESC-derived mesenchymal stem cells (C-hESC-MSCs), which were found to be involved in the metabolic process, immune response, cell signaling, and cell proliferation, as compared to bone marrow derived-MSCs(BM-MSCs). Moreover, these up-regulated proteins were potentially related to the Wnt/β-catenin pathway. These results suggest that C-hESC-MSCs are a highly proliferative cell population, which can interact with the Wnt/β-catenin signaling pathway; thus, due to the upregulated cell survival ability or downregulated apoptosis effects of C-hESC-MSCs, these can be used as an unlimited cellular source in the cell therapy field for a higher therapeutic potential. Overall, the study provided valuable insights into the molecular functioning of hESC derivatives as a valuable cellular source.

• Asian Pacific Journal of Cancer Prevention
• /
• 제14권12호
• /
• pp.7069-7074
• /
• 2013

Programmed cell death is a basic cellular process that is critical to maintaining tissue homeostasis. In contrast to apoptosis, necrosis was previously regarded as an unregulated and uncontrollable process. However, as research has progressed, necrosis, also known as necroptosis or programmed necrosis, is drawing increasing attention, not least becasu of its possible impications for cancer research. Necroptosis exhibits a unique signaling pathway that requires the involvement of receptor interaction protein kinases 1 and 3 (RIP1 and RIP3), mixed lineage kinase domain-like (MLKL), and phosphoglycerate mutase 5 (PGAM5) and can be specifically inhibited by necrostatins. Not only does necroptosis serve as a backup cell death program when apoptosis is inhibited, but it is now recognized to play a pivotal role in regulating various physiological processes and the pathogenesis of a variety of human diseases such as ischemic brain injury, immune system disorders and cancer. The control of necroptosis by various defined trigger factors and signaling pathways now offers the opportunity to target this cellular process for therapeutic purposes. The purpose of this paper is to review current findings concerning the connections between various trigger factors and the RIP1/RIP3 signaling pathway as it relates to necroptosis.

• Animal cells and systems
• /
• 제13권1호
• /
• pp.9-15
• /
• 2009

Eph receptors and their ephrin ligands have been implicated in a variety of cellular processes such as cellular morphogenesis and motility. Our previous studies demonstrated that Odin, one of the Anks family proteins, functions as a scaffolding protein of the EphA8 signaling pathway leading to modulation of cell migration or axonal outgrowth. Here we show that WDR7 is associated with Odin and that it is possibly implicated in the EphA8 signaling pathway. WD40 repeats present in the COOH-terminal region of WDR7 appear to be crucial for its association with Odin, whereas the binding motif of Odin is located in between ankyrin repeats and PTB domain. Co-immunoprecipitation experiments revealed that association of WDR7 with Odin is enhanced by ephrin ligand treatment, possibly through forming large protein complexes including both EphA8 and ephrin-A5. Consistently, immunofluorescence staining experiments suggested that WDR7 constitute a component of the large protein complexes containing Odin, EphA8 and ephrin-A5. Taken together, our results suggest the WDR7-Odin complexes might be involved in the signaling pathway downstream of the EphA8 receptor.

• BMB Reports
• /
• 제35권1호
• /
• pp.24-27
• /
• 2002

Apoptotic cell death is an active process mediated by various signaling pathways, which include the caspase cascade and the stress-activated protein kinase pathways. The caspase cascade is activated by two distinct routes: one from cell surface and the other from mitochondria. Activation of the route from cell surface requires the cellular components that include membrane receptors, adaptor proteins such as TRADD and FADD, and caspase-8, while activation of the other from mitochondria requires Apaf-1, caspase-9, and cytosolic cytochrome c. On the other hand, persistent stimulation of the stress-activated protein kinase pathway is also shown to mediate apoptosis in many cell types. Gene-targeting studies with jnk- or jip-null mice, in particular, strongly suggest that this signaling pathway plays a pivotal role in the cellular machinery for apoptosis.

• BMB Reports
• /
• 제48권6호
• /
• pp.301-302
• /
• 2015

Hypoxia is associated with many pathological conditions as well as the normal physiology of metazoans. We identified a lactate-dependent signaling pathway in hypoxia, mediated by the oxygen- and lactate-regulated protein NDRG family member 3 (NDRG3). Oxygen negatively regulates NDRG3 expression at the protein level via the PHD2/VHL system, whereas lactate, produced in excess under prolonged hypoxia, blocks its proteasomal degradation by binding to NDRG3. We also found that the stabilized NDRG3 protein promotes angiogenesis and cell growth under hypoxia by activating the Raf-ERK pathway. Inhibiting cellular lactate production abolishes NDRG3-mediated hypoxia responses. The NDRG3-Raf-ERK axis therefore provides the genetic basis for lactate-induced hypoxia signaling, which can be exploited for the development of therapies targeting hypoxia-induced diseases in addition to advancing our understanding of the normal physiology of hypoxia responses. [BMB Reports 2015; 48(6): 301-302]

• Nutrition Research and Practice
• /
• 제3권1호
• /
• pp.64-71
• /
• 2009

Amino acids are fundamental nutrients for protein synthesis and cell growth (increase in cell size). Recently, many compelling evidences have shown that the level of amino acids is sensed by extra- or intra-cellular amino acids sensor(s) and regulates protein synthesis/degradation. Mammalian target of rapamycin complex 1 (mTORC1) is placed in a central position in cell growth regulation and dysregulation of mTOR signaling pathway has been implicated in many serious human diseases including cancer, diabetes, and tissue hypertrophy. Although amino acids are the most potent activator of mTORC1, how amino acids activate mTOR signaling pathway is still largely unknown. This is partly because of the diversity of amino acids themselves including structure and metabolism. In this review, current proposed amino acid sensing mechanisms to regulate mTORC1 and the evidences pro/against the proposed models are discussed.

• Molecules and Cells
• /
• 제20권2호
• /
• pp.196-200
• /
• 2005

The neurofibromatosis type2 (NF2) tumor suppressor gene product, merlin, is structurally related to the ezrin-radixin-moesin (ERM) family of proteins that anchor the actin cytoskeleton to specific membrane proteins and participate in cell signaling. However, the basis of the tumor suppressing activity of merlin is not well understood. Previously, we identified a role of merlin as an inhibitor of the Ras-ERK signaling pathway. Recent studies have suggested that phosphorylation of merlin, as of other ERM proteins, may regulate its function. To determine whether phosphorylation of merlin affects its suppression of Ras-ERK signaling, we generated plasmids expressing full-length merlin with substitutions of serine 518, a potential phosphorylation site. A substitution that mimics constitutive phosphorylation (S518D) abrogated the ability of merlin to suppress effects of the Ras-ERK signaling pathway such as Ras-induced SRE transactivation, Elk-mediated SRE transactivation, Ras-induced ERK phosphorylation and Ras-induced focus formation. On the other hand, an S518A mutant, which mimics nonphosphorylated merlin, acted like wild type merlin. These observations show that mimicking merlin phosphorylation impairs not only growth suppression by merlin but also its inhibitory action on the Ras-ERK signaling pathway.

• Molecules and Cells
• /
• 제26권4호
• /
• pp.368-372
• /
• 2008

Recent molecular and genetic studies in rice, a short-day plant, have elucidated both conservation and divergence of photoperiod pathway genes and their regulators. However, the biological roles of rice genes that act within the autonomous pathway are still largely unknown. In order to better understand the function of the autonomous pathway genes in rice, we conducted molecular genetic analyses of OsFVE, a rice gene homologous to Arabidopsis FVE. OsFVE was found to be ubiquitously expressed in vegetative and reproductive organs. Overexpression of OsFVE could rescue the flowering time phenotype of the Arabidopsis fve mutants by up-regulating expression of the SUPPRESSOR OF OVEREXPRESSION OF CO1 (SOC1) and down-regulating FLOWERING LOCUS C (FLC) expression. These results suggest that there may be a conserved function between OsFVE and FVE in the control of flowering time. However, OsFVE overexpression in the fve mutants did not rescue the flowering time phenotype in in relation to the response to intermittent cold treatment.

• Journal of Yeungnam Medical Science
• /
• 제30권1호
• /
• pp.4-9
• /
• 2013

Leptin, a 16-kDa cytokine, is secreted by adipose tissue in response to the surplus of fat store. Thereby, the brain is informed about the body's energy status. In the hypothalamus, leptin triggers specific neuronal subpopulations (e.g., POMC and NPY neurons) and activates several intracellular signaling events, including the JAK/STAT, MAPK, PI3K, and mTOR pathway, which eventually translates into decreased food intake and increased energy expenditure. Leptin signal is inhibited by a feedback inhibitory pathway mediated by SOCS3. PTP1B involves another inhibitory pathway of leptin. Leptin potently promotes fat mass loss and body weight reduction in lean subjects. However, it is not widely used in the clinical field because of leptin resistance, which is a common feature of obesity characterized by hyperleptinemia and the failure of exogenous leptin administration to provide therapeutic benefit in rodents and humans. The potential mechanisms of leptin resistance include the following: 1) increases in circulating leptin-binding proteins, 2) reduced transport of leptin across the blood-brain barrier, 3) decreased leptin receptor-B (LRB), and/or 4) the provocation of processes that diminish cellular leptin signaling (inflammation, endoplasmic reticulum stress, feedback inhibition, etc.). Thus, interference of the cellular mechanisms that attenuate leptin signaling improves leptin action in cells and animal models, suggesting the potential utility of these processes as points of therapeutic intervention. Various experimental trials and compounds that improve leptin resistance are introduced in this paper.