• Molecules and Cells
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• 제42권3호
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• pp.200-209
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• 2019

Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have been used as promising tools for regenerative medicine, disease modeling, and drug screening. Traditional and common strategies for pluripotent stem cell (PSC) differentiation toward disease-relevant cell types depend on sequential treatment of signaling molecules identified based on knowledge of developmental biology. However, these strategies suffer from low purity, inefficiency, and time-consuming culture conditions. A growing body of recent research has shown efficient cell fate reprogramming by forced expression of single or multiple transcription factors. Here, we review transcription factor-directed differentiation methods of PSCs toward neural, muscle, liver, and pancreatic endocrine cells. Potential applications and limitations are also discussed in order to establish future directions of this technique for therapeutic purposes.

• 대한기관식도과학회지
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• 제2권2호
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• pp.200-212
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• 1996

The clinical staging systems for oral squamous cell carcinoma is limited as a prognostic indicatior because of different biological characteristics of cancer in this region and variable microenvironment depending on subsites, there have been study to determine prognosis by evaluating malignancy, that is the nature of tumor cells. Many studies have been tried to determine prognostic indicator in various malignancies for the evaluation of differentiation capacity and the expression of oncogene product. EGF make a role in cellular growth and differentiation and to be essential in cellular survival. EGFR is an intergral membrane protein, stimulate cellular differentiation and hormonal secretion, and has structural homology with V-erb-B transforming protein. Recent reports have demonstrated that EGFR is overexpressed in stomach, breast, vagina, dermis, head and neck, genitourinary and lung tumors, and possibly used as a tumor marker. In head and neck region, most of studies were mainly carried out on laryngeal squamous cell carcinoma. In the present study, immunohistochemical study for EGFR and C-erb-B2 gene in paraffin sections of 45 squamous cell carcinoma in oral cavity was performed to evaluate the presense of EGFR and C- erb-B2 gene in this lesion, to evaluate them as a prognostic indicator by analysing the correlation between these expression and subsites, primary stages, clinical stages, pathologic grades, neck node metastasis, recurrences and treatment results, and to determine relation between EGFR and C-erb-B2 gene.

• Molecules and Cells
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• 제41권11호
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• pp.971-978
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• 2018

The stem cell factor (SCF)/c-KIT axis plays an important role in the hematopoietic differentiation of human pluripotent stem cells (hPSCs), but its regulatory mechanisms involving microRNAs (miRs) are not fully elucidated. Here, we demonstrated that supplementation with SCF increases the hematopoietic differentiation of hPSCs via the interaction with its receptor tyrosine kinase c-KIT, which is modulated by miR-221 and miR-222. c-KIT is comparably expressed in undifferentiated human embryonic and induced pluripotent stem cells. The inhibition of SCF signaling via treatment with a c-KIT antagonist (imatinib) during hPSC-derived hematopoiesis resulted in reductions in the yield and multi-lineage potential of hematopoietic progenitors. We found that the transcript levels of miR-221 and miR-222 targeting c-KIT were significantly lower in the pluripotent state than they were in terminally differentiated somatic cells. Furthermore, suppression of miR-221 and miR-222 in undifferentiated hPSC cultures induced more hematopoiesis by increasing c-KIT expression. Collectively, our data implied that the modulation of c-KIT by miRs may provide further potential strategies to expedite the generation of functional blood cells for therapeutic approaches and the study of the cellular machinery related to hematologic malignant diseases such as leukemia.

• 한국동물학회지
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• 제36권3호
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• pp.433-438
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• 1993

본 연구를 통해서 근세포 융합과정에서 신호 전달물질의 가능성이 제기되고 있는 세포내 cGMP peak가 guanylate cyclase activity의 변화와 관련이 있으며, guanylate cyclase는 L-arginine: NO synthase에 의해서 촉진될 것임을 입증할 수 있는 간접적 증거를 제시한다. 즉, SNP는 근세포의 융합과 guanylate cyclase activity를 아울러 증가시키며, L-arginine: NO synthase inhibitor인 L-NG-monomethyl arginine은 biochemical differentiation에는 영향을 주지 않고 근세포 융합만을 억제한다. 이러한 결과들과 muthylene blue가 근세포의 융합만을 억제하면서도 biochemical differentiation에는 영향을 주지 않으며 guanylate cyclase activity를 억제하는 사실들을 종합해서 생각할 때, 근세포 융합에서 cGMP peak가 guanylate cyclase activity의 활성화와 관련이 있으며, L-arginine: NO synthase가 $Ca^2$+ influx와 guanylate cyclase 사이를 매개할 가능성을 암시한다.

• BMB Reports
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• 제54권9호
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• pp.470-475
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• 2021

Low-dose metronomic chemotherapy has been introduced as a less toxic and effective strategy to inhibit tumor angiogenesis, but its anti-angiogenic mechanism on endothelial progenitor cells (EPCs) has not been fully elucidated. Here, we investigated the functional role of regulated in development and DNA damage response 1 (REDD1), an endogenous inhibitor of mTORC1, in low-dose doxorubicin (DOX)-mediated dysregulation of EPC functions. DOX treatment induced REDD1 expression in bone marrow mononuclear cells (BMMNCs) and subsequently reduced mTORC1-dependent translation of endothelial growth factor (VEGF) receptor (Vegfr)-2 mRNA, but not that of the mRNA transcripts for Vegfr-1, epidermal growth factor receptor, and insulin-like growth factor-1 receptor. This selective event was a risk factor for the inhibition of BMMNC differentiation into EPCs and their angiogenic responses to VEGF-A, but was not observed in Redd1-deficient BMMNCs. Low-dose metronomic DOX treatment reduced the mobilization of circulating EPCs in B16 melanoma-bearing wild-type but not Redd1-deficient mice. However, REDD1 overexpression inhibited the differentiation and mobilization of EPCs in both wild-type and Redd1-deficient mice. These data suggest that REDD1 is crucial for metronomic DOX-mediated EPC dysfunction through the translational repression of Vegfr-2 transcript, providing REDD1 as a potential therapeutic target for the inhibition of tumor angiogenesis and tumor progression.

• Nutrition Research and Practice
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• 제4권4호
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• pp.276-282
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• 2010

The principal objective of this study was to evaluate the chemopreventive and therapeutic effects of a combination of all-trans-retinoic acid (RA) and knockdown of delta-like 1 homologue (Drosophila) (DLK1) on neuroblastoma, the most common malignant disease in children. As unfavorable neuroblastoma is poorly differentiated, neuroblastoma cell was induced differentiation by RA or DLK1 knockdown. Neuroblastoma cells showed elongated neurite growth, a hallmark of neuronal differentiation at various doses of RA, as well as by DLK1 knockdown. In order to determine whether or not a combination of RA and DLK1 knockdown exerts a greater chemotherapeutic effect on neuroblastoma, cells were incubated at 10 nM RA after being transfected with SiRNA-DLK1. Neuronal differentiation was increased more by a combination of RA and DLK1 knockdown than by single treatment. Additionally, in order to assess the signal pathway of neuroblastoma differentiation induced by RA and DLK1 knockdown, treatment with the specific MEK/ERK inhibitors, U0126 and PD 98059, was applied to differentiated neuroblastoma cells. Differentiation induced by RA and DLK1 knockdown increased ERK phosphorylation. The MEK/ERK inhibitor U0126 completely inhibited neuronal differentiation induced by both RA and DLK1 knockdown, whereas PD98059 partially blocked neuronal differentiation. After the withdrawal of inhibitors, cellular differentiation was fully recovered. This study is, to the best of our knowledge, the first to demonstrate that the specific inhibitors of the MEK/ERK pathway, U0126 and PD98059, exert differential effects on the ERK phosphorylation induced by RA or DLK1 knockdown. Based on the observations of this study, it can be concluded that a combination of RA and DLK1 knockdown increases neuronal differentiation for the control of the malignant growth of human neuroblastomas, and also that both MEK1 and MEK2 are required for the differentiation induced by RA and DLK1 knockdown.

• Molecules and Cells
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• 제39권5호
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• pp.389-394
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• 2016

Dovitinib (TKI258) is a small molecule multi-kinase inhibitor currently in clinical phase I/II/III development for the treatment of various types of cancers. This drug has a safe and effective pharmacokinetic/pharmacodynamic profile. Although dovitinib can bind several kinases at nanomolar concentrations, there are no reports relating to osteoporosis or osteoblast differentiation. Herein, we investigated the effect of dovitinib on human recombinant bone morphogenetic protein (BMP)-2-induced osteoblast differentiation in a cell culture model. Dovitinib enhanced the BMP-2-induced alkaline phosphatase (ALP) induction, which is a representative marker of osteoblast differentiation. Dovitinib also stimulated the translocation of phosphorylated Smad1/5/8 into the nucleus and phosphorylation of mitogen-activated protein kinases, including ERK1/2 and p38. In addition, the mRNA expression of BMP-4, BMP-7, ALP, and OCN increased with dovitinib treatment. Our results suggest that dovitinib has a potent stimulating effect on BMP-2-induced osteoblast differentiation and this existing drug has potential for repositioning in the treatment of bone-related disorders.

• BMB Reports
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• 제34권5호
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• pp.421-427
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• 2001

Osteoclasts, cells primarily involved in bone resorption, originate from the hematopoietic precursor cells of the monocyte/macrophage lineage and differentiate into multinucleated mature forms. We developed an in vitro osteoclast culture system using embryonic chicken bone marrow cells. This culture system can be utilized in studies on the differentiation and function of osteoclasts. Phosphatidylinositol 3-kinase (PI3-kinase) and mitogen-activated protein kinases (MAPKs) have been implicated in diverse cellular functions including proliferation, migration, and survival. Using the developed avian osteoclast culture system, we examined the involvement of these kinases in osteoclast differentiation by employing specific inhibitors of the kinases. We Found that the inhibition of the PI 3-kinase, p38, or ERK interfered with osteoclast formation, suggesting that the signaling pathways that involve these molecules participate in the process of chicken osteoclast differentiation.

• Molecules and Cells
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• 제38권4호
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• pp.362-372
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• 2015

Setdb1, an H3-K9 specific histone methyltransferase, is associated with transcriptional silencing of euchromatic genes through chromatin modification. Functions of Setdb1 during development have been extensively studied in embryonic and mesenchymal stem cells as well as neurogenic progenitor cells. But the role of Sedtdb1 in myogenic differentiation remains unknown. In this study, we report that Setdb1 is required for myogenic potential of C2C12 myoblast cells through maintaining the expressions of MyoD and muscle-specific genes. We find that reduced Setdb1 expression in C2C12 myoblast cells severely delayed differentiation of C2C12 myoblast cells, whereas exogenous Setdb1 expression had little effect on. Gene expression profiling analysis using oligonucleotide microarray and RNA-Seq technologies demonstrated that depletion of Setdb1 results in downregulation of MyoD as well as the components of muscle fiber in proliferating C2C12 cells. In addition, exogenous expression of MyoD reversed transcriptional repression of MyoD promoter-driven luciferase reporter by Setdb1 shRNA and rescued myogenic differentiation of C2C12 myoblast cells depleted of endogenous Setdb1. Taken together, these results provide new insights into how levels of key myogenic regulators are maintained prior to induction of differentiation.

• Molecules and Cells
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• 제41권5호
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• pp.444-453
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• 2018

Aberrations in histone modifications are being studied in mixed-lineage leukemia (MLL)-AF9-driven acute myeloid leukemia (AML). In this study, we focused on the regulation of the differentiation of the MLL-AF9 type AML cell line THP-1. We observed that, upon phorbol 12-myristate 13-acetate (PMA) treatment, THP-1 cells differentiated into monocytes by down-regulating Aurora kinase A (AURKA), resulting in a reduction in H3S10 phosphorylation. We revealed that the AURKA inhibitor alisertib accelerates the expression of the H3K27 demethylase KDM6B, thereby dissociating AURKA and YY1 from the KDM6B promoter region. Using Flow cytometry, we found that alisertib induces THP-1 differentiation into monocytes. Furthermore, we found that treatment with the KDM6B inhibitor GSK-J4 perturbed the PMA-mediated differentiation of THP-1 cells. Thus, we discovered the mechanism of AURKA-KDM6B signaling that controls the differentiation of THP-1 cells, which has implications for biotherapy for leukemia.