• BMB Reports
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• v.41 no.12
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• pp.833-839
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• 2008

Angiogenesis in tumors is driven by multiple growth factors that activate receptor tyrosine kinases. An important driving force of angiogenesis in solid tumors is signaling through vascular endothelial growth factor (VEGF) and its receptors (VEGFRs). Angiogenesis inhibitors that target this signaling pathway are now in widespread use for the treatment of cancer. However, when used alone, inhibitors of VEGF/VEGFR signaling do not destroy all blood vessels in tumors and do not slow the growth of most human cancers. VEGF/VEGFR signaling inhibitors are, therefore, used in combination with chemotherapeutic agents or radiation therapy. Additional targets for inhibiting angiogenesis would be useful for more efficacious treatment of cancer. One promising target is the signaling pathway of hepatocyte growth factor (HGF) and its receptor (HGFR, also known as c-Met), which plays important roles in angiogenesis and tumor growth. Inhibitors of this signaling pathway have been shown to inhibit angiogenesis in multiple in vitro and in vivo models. The HGF/c-Met signaling pathway is now recognized as a promising target in cancer by inhibiting angiogenesis, tumor growth, invasion, and metastasis.

• Molecules and Cells
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• v.41 no.4
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• pp.257-263
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• 2018

Vertebrate organ development is accompanied by demarcation of tissue compartments, which grow coordinately with their neighbors. Hence, perturbing the coordinative growth of neighboring tissue compartments frequently results in organ malformation. The growth of tissue compartments is regulated by multiple intercellular and intracellular signaling pathways, including the Hippo signaling pathway that limits the growth of various organs. In the optic neuroepithelial continuum, which is partitioned into the retina, retinal pigment epithelium (RPE) and ciliary margin (CM) during eye development, the Hippo signaling activity operates differentially, as it does in many tissues. In this review, we summarize recent studies that have explored the relationship between the Hippo signaling pathway and growth of optic neuroepithelial compartments. We will focus particularly on the roles of a tumor suppressor, neurofibromin 2 (NF2), whose expression is not only dependent on compartment-specific transcription factors, but is also subject to regulation by a Hippo-Yap feedback signaling circuit.

• BMB Reports
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• v.51 no.3
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• pp.134-142
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• 2018

Organ growth is fundamental to animal development. One of major mechanisms for growth control is mediated by the conserved Hippo signaling pathway initially identified in Drosophila. The core of this pathway in Drosophila consists of a cascade of protein kinases Hippo and Warts that negatively regulate transcriptional coactivator Yorkie (Yki). Activation of Yki promotes cell survival and proliferation to induce organ growth. A key issue in Hippo signaling is to understand how core kinase cascade is activated. Activation of Hippo kinase cascade is regulated in the upstream by at least two transmembrane proteins Crumbs and Fat that act in parallel. These membrane proteins interact with additional factors such as FERM-domain proteins Expanded and Merlin to modulate subcellular localization and function of the Hippo kinase cascade. Hippo signaling is also influenced by cytoskeletal networks and cell tension in epithelia of developing organs. These upstream events in the regulation of Hippo signaling are only partially understood. This review focuses on our current understanding of some upstream processes involved in Hippo signaling in developing Drosophila organs.

• BMB Reports
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• v.52 no.1
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• pp.70-85
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• 2019

Reduction of insulin/insulin-like growth factor 1 (IGF1) signaling (IIS) extends the lifespan of various species. So far, several longevity mouse models have been developed containing mutations related to growth signaling deficiency by targeting growth hormone (GH), IGF1, IGF1 receptor, insulin receptor, and insulin receptor substrate. In addition, p70 ribosomal protein S6 kinase 1 (S6K1) knockout leads to lifespan extension. S6K1 encodes an important kinase in the regulation of cell growth. S6K1 is regulated by mechanistic target of rapamycin (mTOR) complex 1. The v-myc myelocytomatosis viral oncogene homolog (MYC)-deficient mice also exhibits a longevity phenotype. The gene expression profiles of these mice models have been measured to identify their longevity mechanisms. Here, we summarize our knowledge of long-lived mouse models related to growth and discuss phenotypic characteristics, including organ-specific gene expression patterns.

• Archives of Pharmacal Research
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• v.27 no.4
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• pp.361-370
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• 2004

The discovery of insulin receptor substrate (IRS) proteins and their role to link cell surface receptors to the intracellular signaling cascades is a key step to understanding insulin and insulin-like growth factor (IGF) action. Moreover, IRS-proteins coordinate signals from the insulin and IGF receptor tyrosine kinases with those generated by proinflammatory cytokines and nutrients. The IRS2-branch of the insulin/IGF signaling cascade has an important role in both peripheral insulin response and pancreatic $\beta$-cell growth and function. Dysregulation of IRS2 signaling in mice causes the failure of compensatory hyperinsulinemia during peripheral insulin resistance. IRS protein signaling is down regulated by serine phosphorylation or protea-some-mediated degradation, which might be an important mechanism of insulin resistance during acute injury and infection, or chronic stress associated with aging or obesity. Under-standing the regulation and signaling by IRS1 and IRS2 in cell growth, metabolism and survival will reveal new strategies to prevent or cure diabetes and other metabolic diseases.

• The Korean Journal of Physiology and Pharmacology
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• v.20 no.5
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• pp.487-498
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• 2016

Leptin, an adipokine predominantly produced from adipose tissue, is well known to induce tumor growth. However, underlying molecular mechanisms are not established yet. While p53 has long been well recognized as a potent tumor suppressor gene, accumulating evidence has also indicated its potential role in growth and survival of cancer cells depending on experimental environments. In the present study, we examined if p53 signaling is implicated in leptin-induced growth of cancer cells. Herein, we demonstrated that leptin treatment significantly increased p53 protein expression in both hepatic (HepG2) and breast (MCF-7) cancer cells without significant effect on mRNA expression. Enhanced p53 expression by leptin was mediated via modulation of ubiquitination, in particular ubiquitin specific protease 2 (USP2)-dependent manner. Furthermore, gene silencing of p53 by small interfering RNA (siRNA) suppressed leptin-induced growth of hepatic and breast cancer cells, indicating the role of p53 signaling in tumor growth by leptin. In addition, we also showed that knockdown of p53 restored suppression of caspase-3 activity by leptin through modulating Bax expression and prevented leptin-induced cell cycle progression, implying the involvement of p53 signaling in the regulation of both apoptosis and cell cycle progression in cancer cells treated with leptin. Taken together, the results in the present study demonstrated the potential role of p53 signaling in leptin-induced tumor growth.

• Molecules and Cells
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• v.39 no.8
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• pp.587-593
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• 2016

As sessile organisms, plants must be able to adapt to the environment. Plants respond to the environment by adjusting their growth and development, which is mediated by sophisticated signaling networks that integrate multiple environmental and endogenous signals. Recently, increasing evidence has shown that a bHLH transcription factor PIF4 plays a major role in the multiple signal integration for plant growth regulation. PIF4 is a positive regulator in cell elongation and its activity is regulated by various environmental signals, including light and temperature, and hormonal signals, including auxin, gibberellic acid and brassinosteroid, both transcriptionally and post-translationally. Moreover, recent studies have shown that the circadian clock and metabolic status regulate endogenous PIF4 level. The PIF4 transcription factor cooperatively regulates the target genes involved in cell elongation with hormone-regulated transcription factors. Therefore, PIF4 is a key integrator of multiple signaling pathways, which optimizes growth in the environment. This review will discuss our current understanding of the PIF4-mediated signaling networks that control plant growth.

• Journal of mucopolysaccharidosis and rare diseases
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• v.2 no.2
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• pp.46-49
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• 2016

Achondroplasia is autosomal dominant genetic disease and fibroblast growth factor receptor 3 (FGFR3) is currently known to be the only gene that causes achondroplasia. Gain-of function mutation in fibroblast-growth-factor-receptor 3 (FGFR3) causes the disease and C-type natriuretic peptide (CNP) antagonizes FGFR3 downstream signaling by inhibiting the pathway of mitogen-activated protein kinase (MAPK). As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article summaries the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH.

• Journal of Ginseng Research
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• v.48 no.2
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• pp.220-228
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• 2024

Background: Panax ginseng, one of the valuable perennial medicinal plants, stores numerous pharmacological substrates in its storage roots. Given its perennial growth habit, organ regeneration occurs each year, and cambium stem cell activity is necessary for secondary growth and storage root formation. Cytokinin (CK) is a phytohormone involved in the maintenance of meristematic cells for the development of storage organs; however, its physiological role in storage-root secondary growth remains unknown. Methods: Exogenous CK was repeatedly applied to P. ginseng, and morphological and histological changes were observed. RNA-seq analysis was used to elucidate the transcriptional network of CK that regulates P. ginseng growth and development. The HISTIDINE KINASE 3 (PgHK3) and RESPONSE REGULATOR 2 (PgRR2) genes were cloned in P. ginseng and functionally analyzed in Arabidopsis as a two-component system involved in CK signaling. Results: Phenotypic and histological analyses showed that CK increased cambium activity and dormant axillary bud formation in P. ginseng, thus promoting storage-root secondary growth and bud formation. The evolutionarily conserved two-component signaling pathways in P. ginseng were sufficient to restore CK signaling in the Arabidopsis ahk2/3 double mutant and rescue its growth defects. Finally, RNA-seq analysis of CK-treated P. ginseng roots revealed that plant-type cell wall biogenesis-related genes are tightly connected with mitotic cell division, cytokinesis, and auxin signaling to regulate CK-mediated P. ginseng development. Conclusion: Overall, we identified the CK signaling-related two-component systems and their physiological role in P. ginseng. This scientific information has the potential to significantly improve the field-cultivation and biotechnology-based breeding of ginseng.

• Proceedings of the PSK Conference
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• 2003.04a
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• pp.107-108
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• 2003

The epidermal growth factor (EGF) is an important signaling ligand for the mitogenesis of many cells. The EGF receptors use signaling molecule multicomplexes and dynamic protein networks for the transmission and amplification of the signals as well as for the regulation of the cellular responses. EGF signaling has been reported to be enhanced in various tumors by the overexpressed EGF receptor and/or the mediators such as phospholipase C-$\gamma$1(PLC$\gamma$1). (omitted)