• Molecules and Cells
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• 제41권5호
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• pp.381-389
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• 2018

ARF is a tumor suppressor protein that has a pivotal role in the prevention of cancer development through regulating cell proliferation, senescence, and apoptosis. As a factor that induces senescence, the role of ARF as a tumor suppressor is closely linked to the p53-MDM2 axis, which is a key process that restrains tumor formation. Thus, many cancer cells either lack a functional ARF or p53, which enables them to evade cell oncogenic stress-mediated cycle arrest, senescence, or apoptosis. In particular, the ARF gene is a frequent target of genetic and epigenetic alterations including promoter hyper-methylation or gene deletion. However, as many cancer cells still express ARF, pathways that negatively modulate transcriptional or post-translational regulation of ARF could be potentially important means for cancer cells to induce cellular proliferation. These recent findings of regulators affecting ARF protein stability along with its low levels in numerous human cancers indicate the significance of an ARF post-translational mechanism in cancers. Novel findings of regulators stimulating or suppressing ARF function would provide new therapeutic targets to manage cancer- and senescence-related diseases. In this review, we present the current knowledge on the regulation and alterations of ARF expression in human cancers, and indicate the importance of regulators of ARF as a prognostic marker and in potential therapeutic strategies.

• Molecules and Cells
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• 제45권9호
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• pp.603-609
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• 2022

Cells can communicate in a variety of ways, such as by contacting each other or by secreting certain factors. Recently, extracellular vesicles (EVs) have been proposed to be mediators of cell communication. EVs are small vesicles with a lipid bilayer membrane that are secreted by cells and contain DNA, RNAs, lipids, and proteins. These EVs are secreted from various cell types and can migrate and be internalized by recipient cells that are the same or different than those that secrete them. EVs harboring various components are involved in regulating gene expression in recipient cells. These EVs may also play important roles in the senescence of cells and the accumulation of senescent cells in the body. Studies on the function of EVs in senescent cells and the mechanisms through which nonsenescent and senescent cells communicate through EVs are being actively conducted. Here, we summarize studies suggesting that EVs secreted from senescent cells can promote the senescence of other cells and that EVs secreted from nonsenescent cells can rejuvenate senescent cells. In addition, we discuss the functional components (proteins, RNAs, and other molecules) enclosed in EVs that enter recipient cells.

• Asian Pacific Journal of Cancer Prevention
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• 제14권11호
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• pp.6549-6556
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• 2013

Leukemia stem cells (LSCs) play important roles in leukemia initiation, progression and relapse, and thus represent a critical target for therapeutic intervention. Hence, it is extremely urgent to explore new therapeutic strategies directly targeting LSCs for acute myelogenous leukemia (AML) therapy. We show here that Angelica sinensis polysaccharide (ASP), a major active component in Dong quai (Chinese Angelica sinensis), effectively inhibited human AML $CD34^+CD38^-$ cell proliferation in vitro culture in a dose-dependent manner while sparing normal hematopoietic stem and progenitor cells at physiologically achievable concentrations. Furthermore, ASP exerted cytotoxic effects on AML K562 cells, especially LSC-enriched $CD34^+CD38^-$ cells. Colony formation assays further showed that ASP significantly suppressed the formation of colonies derived from AML $CD34^+CD38^-$ cells but not those from normal $CD34^+CD38^-$ cells. Examination of the underlying mechanisms revealed that ASP induced $CD34^+CD38^-$ cell senescence, which was strongly associated with a series of characteristic events, including up-regulation of p53, p16, p21, and Rb genes and changes of related cell cycle regulation proteins P16, P21, cyclin E and CDK4, telomere end attrition as well as repression of telomerase activity. On the basis of these findings, we propose that ASP represents a potentially important agent for leukemia stem cell-targeted therapy.

• Biomolecules & Therapeutics
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• 제31권6호
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• pp.629-639
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• 2023

Cardiovascular diseases (CVDs) are the most common cardiovascular system disorders. Cellular senescence is a key mechanism associated with dysfunction of aged vascular endothelium. Hyaluronic acid and proteoglycan link protein 1 (HAPLN1) has been known to non-covalently link hyaluronic acid (HA) and proteoglycans (PGs), and forms and stabilizes HAPLN1-containing aggregates as a major component of extracellular matrix. Our previous study showed that serum levels of HAPLN1 decrease with aging. Here, we found that the HAPLN1 gene expression was reduced in senescent human umbilical vein endothelial cells (HUVECs). Moreover, a recombinant human HAPLN1 (rhHAPLN1) decreased the activity of senescence-associated β-gal and inhibited the production of senescence-associated secretory phenotypes, including IL-1β, CCL2, and IL-6. rhHAPLN1 also downregulated IL-17A levels, which is known to play a key role in vascular endothelial senescence. In addition, rhHAPLN1 protected senescent HUVECs from oxidative stress by reducing cellular reactive oxygen species levels, thus promoting the function and survival of HUVECs and leading to cellular proliferation, migration, and angiogenesis. We also found that rhHAPLN1 not only increases the sirtuin 1 (SIRT1) levels, but also reduces the cellular senescence markers levels, such as p53, p21, and p16. Taken together, our data indicate that rhHAPLN1 delays or inhibits the endothelial senescence induced by various aging factors, such as replicative, IL-17A, and oxidative stress-induced senescence, thus suggesting that rhHAPLN1 may be a promising therapeutic for CVD and atherosclerosis.

• 생명과학회지
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• 제18권3호
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• pp.344-349
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• 2008

이 논문에서는 신생아와 노인 유래의 섬유아세포들의 노화의 특징들을 비교하여 사람의 나이와 세포의 수명 및 세포 형질의 관계에 대해 연구하였다. 본 연구의 결과는 비록 한가지의 노인세포에 대해 얻어진 것이기는 하지만 다음과 같은 세 가지 중요한 가능성을 제시한다. 첫째로, 노인에서 유래한 섬유아세포의 증식속도가 신생아 유래의 세포에 비해서 느릴 가능성이 있다. 이러한 결과는 실제로 노인 신체에 존재하는 세포가 신생아에 존재하는 세포에 비해 낮은 속도로 증식할 가능성을 시사하는 것으로서, 노인에서 관찰되는 조직실질의 감소 원인을 설명하는 자료가 될 수 있겠다. 둘째로, 노인 유래 섬유아세포의 early passage 세포가 신생아 유래의 세포의 early passage 세포와 동일하게 낮은 수준의 SA ${\beta}-Gal$ 활성, autofluorescence, lysosome 함량, 그리고 활성산소 수준을 갖고 있었다. 이 점은, early passage 때의 세포가 보이는 형질이 신체에 존재하는 세포의 상황과 크게 다르지 않다고 가정할 때, 노인 신체의 조직에 존재하는 세포들이 신생아의 세포와 유사한 상태로 존재할 가능성을 시사하는 것이다. 즉, 노인 신체에서는 in vitro 노화세포에서 나타나는 수준의 세포노화가 일어나 있지 않다는 것이다. 셋째, 노인세포가 노화했을 때는 신생아세포의 경우와 거의 동일한 수준의 활성산소, lysosome, SA ${\beta}-Gal$ activity 증가를 보이고 있었는데, 이는 노인 유래의 세포가 in vitro 배양 시 신생아 유래의 세포보다 더 심하거나 또는 빠른 산화적 손상이나 세포학적 변화를 겪지는 않는다는 것을 보여주는 것으로서, 세포가 보유한 항산화적 기능이 노인이 되면서 크게 약화되지는 않음을 시사하고 있다. 결론적으로 노인 유래의 세포는 세포증식 속도를 제외하면 대체로 신생아 때의 상태와 동일한 세포 내 상태를 갖고 있다고 결론 내릴 수 있겠다.

• 생명과학회지
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• 제34권8호
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• pp.594-607
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• 2024

다양한 종류의 플라스틱 제품이 오랫동안 산업 및 생활 제품 분야에서 널리 사용되고 있다. 플라스틱 제품에서 파생된 크기가 작은 플라스틱 입자인 MPs와 NPs는 흡입, 섭취 또는 피부 접촉을 통해 인체 내로 유입될 수 있다. 세포 내 이입을 통해 세포 안으로 들어온 MNPs는 세포의 자가 포식을 활성화할 수 있지만, 리소좀 기능 장애로 인해 자가포식 플럭스가 차단될 수 있다. 나아가 세포질에 축적된 그들은 ROS 생성으로 인한 산화적 스트레스, 미토콘드리아 기능 장애, 염증 반응 증가 등과 같은 다양한 스트레스를 유발할 수 있다. 한편 많은 질병과 연관된 세포 노화는 노화의 특징으로, 세포 손상과 스트레스에 반응하여 세포 주기가 안정적으로 종료되는 것으로 정의된다. 특히 세포 노화 유도의 핵심 인자인 산화적 스트레스의 축적은 주요 노화 표지 인자들이 발현을 유도하고, 노화 세포는 염증성 cytokine과 chemokine을 포함한 SASP의 분비를 증가시킨다. 최근 MNPs에 의한 세포 노화 유도에 대한 관심이 높아지고 있지만, 이들에 의한 세포 노화 개시의 기전 및 치료 표적에 대한 연구는 여전히 부족한 실정이다. 따라서 이 총설에서는 MNPs로 인한 다양한 인체 기관계를 구성하는 주요 세포의 세포 노화 유도에 대한 최근 연구 동향을 파악하는데 중점을 두었으며, 아울러 이를 극복하기 위한 방향을 제시하였다.

• BMB Reports
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• 제52권1호
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• pp.42-46
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• 2019

Cellular senescence, a process of cell proliferation arrest in response to various stressors, has been considered to be important factor in age-related disease. Identification of senescent cells in tissues is limited and the role of senescent cells is poorly understood. Recently however, several studies showed the characterization of senescent cells in various pathologic conditions and the role of senescent cells in disease progression is becoming important. Senescent cells are growth-arrested cells, however, the senescence associated secretory phenotype (SASP) of senescent cells could modify the tissues' microenvironment. Here, we discuss the progress and understanding of the role of senescent cells in tissues of pathologic conditions and discuss the development of new therapeutic paradigms, such as senescent cells-targeted therapy.

• Molecules and Cells
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• 제43권4호
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• pp.397-407
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• 2020

DNAJB9 is known to be a member of the molecular chaperone gene family, whose cellular function has not yet been fully characterized. Here, we investigated the cellular function of DNAJB9 under strong mitogenic signals. We found that DNAJB9 inhibits p53-dependent oncogene-induced senescence (OIS) and induces neoplastic transformation under oncogenic RAS activation in mouse primary fibroblasts. In addition, we observed that DNAJB9 interacts physically with p53 under oncogenic RAS activation and that the p53-interacting region of DNAJB9 is critical for the inhibition of p53-dependent OIS and induction of neoplastic transformation by DNAJB9. These results suggest that DNAJB9 induces cell transformation under strong mitogenic signals, which is attributable to the inhibition of p53-dependent OIS by physical interactions with p53. This study might contribute to our understanding of the cellular function of DNAJB9 and the molecular basis of cell transformation.

• Molecules and Cells
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• 제43권7호
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• pp.645-661
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• 2020

Leaf senescence is a developmental process by which a plant actively remobilizes nutrients from aged and photosynthetically inefficient leaves to young growing ones by disassembling organelles and degrading macromolecules. Senescence is accelerated by age and environmental stresses such as prolonged darkness. Phytochrome B (phyB) inhibits leaf senescence by inhibiting phytochrome-interacting factor 4 (PIF4) and PIF5 in prolonged darkness. However, it remains unknown whether phyB mediates the temperature signal that regulates leaf senescence. We found the light-activated form of phyB (Pfr) remains active at least four days after a transfer to darkness at 20℃ but is inactivated more rapidly at 28℃. This faster inactivation of Pfr further increases PIF4 protein levels at the higher ambient temperature. In addition, PIF4 mRNA levels rise faster after the transfer to darkness at high ambient temperature via a mechanism that depends on ELF3 but not phyB. Increased PIF4 protein then binds to the ORE1 promoter and activates its expression together with ABA and ethylene signaling, accelerating leaf senescence at high ambient temperature. Our results support a role for the phy-PIF signaling module in integrating not only light signaling but also temperature signaling in the regulation of leaf senescence.

• Journal of Ginseng Research
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• 제36권1호
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• pp.78-85
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• 2012

Endothelial progenitor cells (EPC) are a population of cells that circulate in the blood stream. They play a role in angiogenesis and, therefore, can be prognostic markers of vascular repair. Ginsenoside $Rg_3$ prevents endothelial cell apoptosis through the inhibition of the mitochondrial caspase pathway. It also affects estrogen activity, which reduces EPC senescence. Sun ginseng (SG), which is heat-processed ginseng, has a high content of ginsenosides. The purpose of this study was to investigate the protective effects of SG on senescence-associated apoptosis in EPCs. In order to isolate EPCs, mononuclear cells of human blood buffy coats were cultured and characterized by their uptake of acetylated low-density lipoprotein (acLDL) and their binding of Ulex europaeus agglutinin I (ulex-lectin). Flow cytometry with annexin-V staining was performed in order to assess early and late apoptosis. Senescence was determined by ${\beta}$-galactosidase (${\beta}$-gal) staining. Staining with 4'-6-Diamidino-2-phenylindole verified that most adherent cells (93${\pm}$2.7%) were acLDL-positive and ulex-lectin-positive. The percentage of ${\beta}$-gal-positive EPCs was decreased from 93.8${\pm}$2.0% to 62.5${\pm}$3.6% by SG treatment. A fluorescence-activated cell sorter (FACS) analysis showed that 4.9% of EPCs were late apoptotic in controls. Sun ginseng decreased the apoptotic cell population by 39% in the late stage of apoptosis from control baseline levels. In conclusion, these results show antisenescent and antiapoptotic effects of SG in human-derived EPCs, indicating that SG can enhance EPC-mediated repair mechanisms.