Publications by authors named "Jeong Su Oh"

55 Publications

RASSF1A Regulates Spindle Organization by Modulating Tubulin Acetylation via SIRT2 and HDAC6 in Mouse Oocytes.

Front Cell Dev Biol 2020 26;8:601972. Epub 2020 Oct 26.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea.

Dynamic changes in microtubules during cell cycle progression are essential for spindle organization to ensure proper segregation of chromosomes. There is growing evidence that post translational modifications of tubulins are the key factors that contribute to microtubule dynamics. However, how dynamic properties of microtubules are regulated in mouse oocytes is unclear. Here, we show that tumor suppressor RASSF1A is required for tubulin acetylation by regulating SIRT2 and HDAC6 during meiotic maturation in mouse oocytes. We found that RASSF1A was localized at the spindle microtubules in mouse oocytes. Knockdown of RASSF1A perturbed meiotic progression by impairing spindle organization and chromosome alignment. Moreover, RASSF1A knockdown disrupted kinetochore-microtubule (kMT) attachment, which activated spindle assembly checkpoint and increased the incidence of aneuploidy. In addition, RASSF1A knockdown decreased tubulin acetylation by increasing SIRT2 and HDAC6 levels. Notably, defects in spindle organization and chromosome alignment after RASSF1A knockdown were rescued not only by inhibiting SIRT2 or HDAC6 activity, but also by overexpressing acetylation mimicking K40Q tubulin. Therefore, our results demonstrated that RASSF1A regulates SIRT2- and HDAC6-mediated tubulin acetylation for proper spindle organization during oocyte meiotic maturation.
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http://dx.doi.org/10.3389/fcell.2020.601972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649257PMC
October 2020

MKI-1, a Novel Small-Molecule Inhibitor of MASTL, Exerts Antitumor and Radiosensitizer Activities Through PP2A Activation in Breast Cancer.

Front Oncol 2020 29;10:571601. Epub 2020 Sep 29.

Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.

Although MASTL (microtubule-associated serine/threonine kinase-like) is an attractive target for anticancer treatment, MASTL inhibitors with antitumor activity have not yet been reported. In this study, we have presented a novel MASTL inhibitor, MKI-1, identified through screening and analysis. Our data revealed that MKI-1 exerted antitumor and radiosensitizer activities in and models of breast cancer. The mechanism of action of MKI-1 occurred through an increase in PP2A activity, which subsequently decreased the c-Myc protein content in breast cancer cells. Moreover, the activity of MKI-1 in the regulation of MASTL-PP2A was validated in a mouse oocyte model. Our results have demonstrated a new small-molecule inhibitor of MASTL, MKI-1, which exerts antitumor and radiosensitizer activities through PP2A activation in breast cancer and
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http://dx.doi.org/10.3389/fonc.2020.571601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7550800PMC
September 2020

Mis12 controls cyclin B1 stabilization via Cdc14B-mediated APC/C regulation during meiotic G2/M transition in mouse oocytes.

Development 2020 04 27;147(8). Epub 2020 Apr 27.

Department of Integrative Biotechnology, Sungkyunkwan University, Suwon, 16419, Korea

Mammalian oocytes are arrested at G2/prophase of the first meiosis. After a hormone surge, oocytes resume meiosis, undergoing germinal vesicle breakdown (GVBD). This process is regulated by Cdk1/cyclin B1. Here, we report that Mis12 is required for G2/M transition by regulating cyclin B1 accumulation via Cdc14B-mediated APC/C regulation, but is not essential for spindle and chromosome dynamics during meiotic maturation. Depletion of Mis12 severely compromised GVBD by impairing cyclin B1 accumulation. Importantly, impaired GVBD after Mis12 depletion was rescued not only by overexpressing cyclin B1 but also by depleting Cdc14B or Cdh1. Notably, oocytes rescued by cyclin B1 overexpression exhibited normal spindle and chromosome organization with intact kinetochore-microtubule attachments. In addition, after being rescued by cyclin B1 overexpression, Mis12-depleted oocytes normally extruded polar bodies. Moreover, Mis12-depleted oocytes formed pronuclear structures after fertilization but failed to develop beyond zygotes. Interestingly, Mis12 was localized in the cytoplasm and spindle poles in oocytes, in contrast to kinetochore localization in somatic cells. Therefore, our results demonstrate that Mis12 is required for meiotic G2/M transition but is dispensable for meiotic progression through meiosis I and II.
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http://dx.doi.org/10.1242/dev.185322DOI Listing
April 2020

Prevention of quality decline and delivery of siRNA using exogenous TCTP translocation across the zona pellucida in mouse oocytes.

Sci Rep 2019 12 11;9(1):18845. Epub 2019 Dec 11.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea.

The delivery of exogenous molecules into mammalian oocytes or embryos has been a challenge because of the existence of the protective zona pellucida (ZP) surrounding the oocyte membrane. Here we show that exogenous translationally controlled tumor protein (TCTP) is able to translocate into oocytes across the ZP and prevents quality deterioration during in vitro culture. Recombinant TCTP-mCherry added to culture media were incorporated into oocytes after passing through the ZP. After internalization, recombinant TCTP-mCherry were enriched at the cortex with wide distribution within the cytoplasm. This translocation capacity of TCTP is dependent on its N-terminal protein transduction domain (PTD). Moreover, translocated recombinant TCTP-mCherry reduced quality deterioration of oocytes during prolonged in vitro culture, which in turn improved fertilization and early embryo development. Furthermore, conjugates between PTD of TCTP and cyclin B1 siRNAs internalized into the cytoplasm of oocytes and downregulated cyclin B1 level. Therefore, our results are the first to show that TCTP has the ability to translocate into oocyte cytoplasm penetrating through the ZP, providing the possibility for preserving oocyte quality during extended in vitro culture and for delivering siRNAs into mouse oocytes.
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http://dx.doi.org/10.1038/s41598-019-55449-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906282PMC
December 2019

Erratum: Cuvette-Type LSPR Sensor for Highly Sensitive Detection of Melamine in Infant Formulas. 2018, 3839.

Sensors (Basel) 2019 Oct 24;19(21). Epub 2019 Oct 24.

Department of Biological Engineering, Inha University, Incheon 402-751, Korea.

The authors wish to make the following erratum to this paper [...].
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http://dx.doi.org/10.3390/s19214630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864865PMC
October 2019

Cuvette-Type LSPR Sensor for Highly Sensitive Detection of Melamine in Infant Formulas.

Sensors (Basel) 2019 Sep 5;19(18). Epub 2019 Sep 5.

Department of Biological Engineering, Inha University, Incheon 402-751, Korea.

The globalization of food distribution has made necessary to secure safe products to the general consumers through the rapid detection of harmful additives on the field. For this purpose, we developed a cuvette-type localized surface plasmon resonance (LSPR) sensor that can be easily used by consumers with conventional ultraviolet-visible light spectrophotometer for measurements. Gold nanoparticles were uniformly deposited on a transparent substrate via a self-assembly method to obtain a plasmonically active chip, and the chemical receptor p-nitroaniline (-NA) was functionalized to stabilize the device sensitivity under external temperature and pH conditions. The fabricated chip was fixed onto a support and combined with a cuvette-type LSPR sensor. To evaluate the applicability of this sensor on the field, sensitivity and quantitative analysis experiments were conducted onto melamine as a model sample from harmful food additives. Under optimal reaction condition (2 mM -NA for 20 min), we achieved an excellent detection limit (0.01 ppb) and a dynamic range allowing quantitative analysis over a wide concentration range (0.1-1000 ppb) from commercially available milk powder samples.
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http://dx.doi.org/10.3390/s19183839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766901PMC
September 2019

Melatonin protects mouse oocytes from DNA damage by enhancing nonhomologous end-joining repair.

J Pineal Res 2019 Nov 22;67(4):e12603. Epub 2019 Aug 22.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Korea.

Mammalian oocytes remain arrested at the first prophase of meiosis in ovarian follicles for an extended period. During this protracted arrest, oocytes are remarkably susceptible to the accumulation of DNA damage. Melatonin (N-acetyl-5-methoxytryptamine), a hormone secreted by the pineal gland, has diverse effects on various physiological processes. However, the effect of melatonin on DNA damage response in mammalian oocytes has not been explored. Here, we showed that melatonin protected mouse oocytes from DNA damage induced by double-strand breaks (DSBs) during prophase arrest and subsequently improved oocyte quality. We found that DNA damage during prophase arrest impaired subsequent meiotic maturation and deteriorated oocyte quality, increasing chromosome fragmentation, spindle abnormality, mitochondrial aggregation, and oxidative stress. However, melatonin treatment during DNA damage accumulation at prophase improved meiotic maturation and relieved the quality decline of oocytes. In addition, melatonin inhibited the accumulation of DNA damage during prophase arrest by reducing the γ-H2AX levels. Although activated ATM levels were decreased by melatonin treatment, the effect of melatonin on DNA damage response was not a direct consequence of ATM inhibition. Instead, melatonin enhanced DNA repair via nonhomologous end-joining (NHEJ) pathway. Interestingly, these actions of melatonin on DNA damage response are receptor-independent in mouse oocytes. Therefore, our results demonstrated that melatonin protects oocytes from DNA damage during prophase arrest by enhancing DNA repair via NHEJ and subsequently prevents the deterioration of oocyte quality during meiotic maturation.
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http://dx.doi.org/10.1111/jpi.12603DOI Listing
November 2019

Identification of a novel embryo-prevalent gene, , involved in preimplantation embryogenesis in mice.

FASEB J 2019 10 19;33(10):11326-11337. Epub 2019 Jul 19.

School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, South Korea.

In mammals, the early embryo travels down the oviduct to the uterus and prepares for implantation. The unique features of preimplantation development include compaction followed by blastocyst formation. This first cell lineage specification involves various proteins including cell polarity regulators, kinases, and transcription factors. In this study, a novel gene named predicted gene 11545 () expressed predominantly in mouse early embryos was identified and characterized at the transcript, protein, cellular, and functional levels. The Gm11545 protein localized to both cytoplasmic and membrane regions of preimplantation embryos. Remarkably, knockdown of led to arrest of mouse embryos at the morula stage and consequent impairment of blastocyst formation. Expression patterns of the key transcription factors critical for early lineage specification, octamer-binding transcription factor 4 and caudal type homeobox 2, were affected by depletion. Based on the collective findings, we propose that the novel protein identified in this study, Gm11545, is implicated in cell proliferation and cell lineage specification critical for blastocyst formation.-Kim, J., Kim, J., Jeong, J., Hong, S. H., Kim, D., Choi, S., Choi, I., Oh, J. S., Cho, C. Identification of a novel embryo-prevalent gene, , involved in preimplantation embryogenesis in mice.
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http://dx.doi.org/10.1096/fj.201900370RRDOI Listing
October 2019

Zw10 is a spindle assembly checkpoint protein that regulates meiotic maturation in mouse oocytes.

Histochem Cell Biol 2019 Sep 27;152(3):207-215. Epub 2019 Jun 27.

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Korea.

Faithful chromosome segregation during the cell cycle is ensured by the spindle assembly checkpoint (SAC). Although SAC activity is highly conserved and most organisms share common SAC components, additional proteins that regulate SAC activity to ensure high fidelity chromosome segregation are present in higher eukaryotes. Zw10 is one of these additional SAC components. Although Zw10 has been demonstrated to be involved in SAC activity during mitosis, little is known about its role during oocyte meiosis. Here, we report that Zw10 is localized at the kinetochore and is required for SAC activation during meiotic maturation. Knockdown of Zw10 led to precocious polar body extrusion by impairing Mad2 recruitment at kinetochores. Moreover, Zw10 knockdown impaired chromosome alignment and kinetochore-microtubule attachment, increasing the incidence of aneuploidy. Furthermore, Zw10 expression decreased with maternal age, suggesting that Zw10 is associated with the age-related increase in the incidence of aneuploidy. Together, our results demonstrate that Zw10 is localized at kinetochores and functions as an essential SAC component in mouse oocytes.
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http://dx.doi.org/10.1007/s00418-019-01800-9DOI Listing
September 2019

MASTL inhibition promotes mitotic catastrophe through PP2A activation to inhibit cancer growth and radioresistance in breast cancer cells.

BMC Cancer 2018 Jul 5;18(1):716. Epub 2018 Jul 5.

Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 215-4 Gongneung-Dong, Nowon-Ku, Seoul, 139-706, South Korea.

Background: Although MASTL (microtubule-associated serine/threonine kinase-like) is a key mitotic kinase that regulates mitotic progression through the inactivation of tumor suppressor protein phosphatase 2A (PP2A), the antitumor mechanism of MASTL targeting in cancer cells is still unclear.

Methods: MASTL expression was evaluated by using breast cancer tissue microarrays and public cancer databases. The effects of MASTL depletion with siRNAs were evaluated in various breast cancer cells or normal cells. Various methods, including cell viability, cell cycle, soft agar, immunoblotting, immunofluorescence, PP2A activity, live image, and sphere forming assay, were used in this study.

Results: This study showed the oncosuppressive mechanism of MASTL targeting that promotes mitotic catastrophe through PP2A activation selectively in breast cancer cells. MASTL expression was closely associated with tumor progression and poor prognosis in breast cancer. The depletion of MASTL reduced the oncogenic properties of breast cancer cells with high MASTL expression, but did not affect the viability of non-transformed normal cells with low MASTL expression. With regard to the underlying mechanism, we found that MASTL inhibition caused mitotic catastrophe through PP2A activation in breast cancer cells. Furthermore, MASTL depletion enhanced the radiosensitivity of breast cancer cells with increased PP2A activity. Notably, MASTL depletion dramatically reduced the formation of radioresistant breast cancer stem cells in response to irradiation.

Conclusion: Our data suggested that MASTL inhibition promoted mitotic catastrophe through PP2A activation, which led to the inhibition of cancer cell growth and a reversal of radioresistance in breast cancer cells.
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http://dx.doi.org/10.1186/s12885-018-4600-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034325PMC
July 2018

Centrosome Clustering Is a Tumor-selective Target for the Improvement of Radiotherapy in Breast Cancer Cells.

Anticancer Res 2018 Jun;38(6):3393-3400

Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

Background/aim: Owing to the frequent observation of centrosome amplification in human cancers, cancer cells have a unique mechanism to suppress detrimental multipolar division by clustering multiple centrosomes into two functional spindle poles, known as centrosome clustering. This study investigated whether inhibition of centrosome clustering enhances the radiation sensitivity of breast cancer cells.

Materials And Methods: In this study, inhibition of centrosome clustering was examined by using various centrosome-declustering agents and KIFC1 siRNA in three breast cancer cell lines and two normal fibroblast cell lines. The combination effect of radiation and centrosome declustering was evaluated by cell viability, clonogenic, immunofluorescence assay.

Results: This study showed that targeting centrosome clustering enhanced the efficacy of radiotherapy of breast cancer cells with less damage to normal cells. Ionizing radiation induced centrosome amplification in breast cancer cells, but not in normal fibroblast cells. Notably, we showed that centrosome declustering efficiently radiosensitized the centrosome-amplified breast cancer cells through induction of multipolar spindles but did not affect the viability of normal fibroblasts in response to irradiation. Furthermore, KIFC1 mediated the radiosensitivity of the centrosome-amplified breast cancer cells.

Conclusion: Our data provided the first evidence that centrosome clustering is a tumor-selective target for the improvement of radiotherapy in breast cancer cells.
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http://dx.doi.org/10.21873/anticanres.12606DOI Listing
June 2018

WIP1 phosphatase suppresses the DNA damage response during G2/prophase arrest in mouse oocytes.

Biol Reprod 2018 10;99(4):798-805

Department of Integrative Biotechnology, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea.

Maternal DNA damage during meiosis causes genetic abnormalities that can lead to infertility, birth defects, and abortion. While DNA damage can rapidly halt cell cycle progression and promote DNA repair in somatic cells, mammalian oocytes are unable to mount a robust G2/prophase arrest in response to DNA damage unless damage levels are severe. Here, we show that inhibition of WIP1 phosphatase enhances the ability of oocytes to respond to DNA damage. We found that WIP1 was expressed constantly during meiotic maturation, and that inhibition of WIP1 activity did not impair meiotic maturation. However, oocytes in G2/prophase were sensitized to DNA damage following WIP1 inhibition, not only increasing γ-H2AX level and ATM phosphorylation, but also decreasing entry into meiosis. Moreover, WIP1 inhibition significantly promoted the repair of damaged DNA during G2/prophase arrest, suggesting that WIP1 suppresses DNA repair in oocytes. Therefore, our results suggest that WIP1 is a key suppressor of the DNA damage response during G2/prophase arrest in mouse oocytes.
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http://dx.doi.org/10.1093/biolre/ioy108DOI Listing
October 2018

Thrombospondin-1 secreted by human umbilical cord blood-derived mesenchymal stem cells rescues neurons from synaptic dysfunction in Alzheimer's disease model.

Sci Rep 2018 01 10;8(1):354. Epub 2018 Jan 10.

Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd, Gyeonggi-do, Republic of Korea.

Alzheimer's disease (AD) is an incurable neurodegenerative disease characterised clinically by learning and memory impairments. Amyloid beta (Aβ) peptide-induced synaptic dysfunction is a pathological process associated with early-stage AD. Here, we show that paracrine action of human umbilical cord blood-derived-mesenchymal stem cells (hUCB-MSCs) protects the hippocampus from synaptic-density loss in in vitro and in vivo AD models. To identify paracrine factors underlying this rescue effect, we analysed hUCB-MSCs' secretome co-cultured with Aβ42-treated mouse hippocampal neurons. Thrombospondin-1 (TSP-1), a protein secreted by hUCB-MSCs in in vitro and 5XFAD AD mouse models, was selected for study. Treatment with exogenous recombinant TSP-1 or co-cultures with hUCB-MSCs significantly increased expression of synaptic-density markers, such as synaptophysin (SYP) and post-synaptic density protein-95 (PSD-95) in Aβ42-treated mouse hippocampal neurons. Knockdown of TSP-1 expression in hUCB-MSCs through small interfering RNA (siRNA) abolished the reversal of Aβ42-induced hippocampal synaptic-density loss. We demonstrate that the rescue effect of hUCB-MSC-secreted TSP-1 was mediated by neuroligin-1 (NLGN1) or α2δ-1 receptors. Interestingly, NLGN1 and α2δ-1 expression, which was reduced in Aβ42-treated hippocampal neurons, increased in co-cultures with hUCB-MSCs or exogenous TSP-1. Together, these findings suggest that hUCB-MSCs can attenuate Aβ42-induced synaptic dysfunction by regulating TSP-1 release, thus providing a potential alternative therapeutic option for early-stage AD.
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http://dx.doi.org/10.1038/s41598-017-18542-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762817PMC
January 2018

CIP2A acts as a scaffold for CEP192-mediated microtubule organizing center assembly by recruiting Plk1 and aurora A during meiotic maturation.

Development 2017 10 21;144(20):3829-3839. Epub 2017 Sep 21.

Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 16419, Korea

In somatic cells spindle microtubules are nucleated from centrosomes that act as major microtubule organizing centers (MTOCs), whereas oocytes form meiotic spindles by assembling multiple acentriolar MTOCs without canonical centrosomes. Aurora A and Plk1 are required for these events, but the underlying mechanisms remain largely unknown. Here we show that CIP2A regulates MTOC organization by recruiting aurora A and Plk1 at spindle poles during meiotic maturation. CIP2A colocalized with pericentrin at spindle poles with a few distinct cytoplasmic foci. Although CIP2A has been identified as an endogenous inhibitor of protein phosphatase 2A (PP2A), overexpression of CIP2A had no effect on meiotic maturation. Depletion of CIP2A perturbed normal spindle organization and chromosome alignment by impairing MTOC organization. Importantly, CIP2A was reciprocally associated with CEP192, promoting recruitment of aurora A and Plk1 at MTOCs. CIP2A was phosphorylated by Plk1 at S904, which targets CIP2A to MTOCs and facilitates MTOC organization with CEP192. Our results suggest that CIP2A acts as a scaffold for CEP192-mediated MTOC assembly by recruiting Plk1 and aurora A during meiotic maturation in mouse oocytes.
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http://dx.doi.org/10.1242/dev.158584DOI Listing
October 2017

Antihelminthic drug niclosamide inhibits CIP2A and reactivates tumor suppressor protein phosphatase 2A in non-small cell lung cancer cells.

Biochem Pharmacol 2017 11 13;144:78-89. Epub 2017 Aug 13.

Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea; Radiological and Medico-Oncological Sciences, University of Science and Technology, South Korea. Electronic address:

Protein phosphatase 2A (PP2A) is a critical tumor suppressor complex responsible for the inactivation of various oncogenes. Recently, PP2A reactivation has emerged asan anticancer strategy. Cancerous inhibitor of protein phosphatase 2A (CIP2A), an endogenous inhibitor of PP2A, is upregulated in many cancer cells, including non-small cell lung cancer (NSCLC) cells. We demonstrated that the antihelminthic drug niclosamide inhibited the expression of CIP2A and reactivated the tumor suppressor PP2A in NSCLC cells. We performed a drug-repurposing screen and identified niclosamide asa CIP2A suppressor in NSCLC cells. Niclosamide inhibited cell proliferation, colony formation, and tumor sphere formation, and induced mitochondrial dysfunction through increased mitochondrial ROS production in NSCLC cells; however, these effects were rescued by CIP2A overexpression, which indicated that the antitumor activity of niclosamide was dependent on CIP2A. We found that niclosamide increased PP2A activity through CIP2A inhibition, which reduced the phosphorylation of several oncogenic proteins. Moreover, we found that a niclosamide analog inhibited CIP2A expression and increased PP2A activity in several types of NSCLC cells. Finally, we showed that other well-known PP2A activators, including forskolin and FTY720, did not inhibit CIP2A and that their activities were not dependent on CIP2A. Collectively, our data suggested that niclosamide effectively suppressed CIP2A expression and subsequently activated PP2A in NSCLC cells. This provided strong evidence for the potential use of niclosamide asa PP2A-activating drug in the clinical treatment of NSCLC.
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http://dx.doi.org/10.1016/j.bcp.2017.08.009DOI Listing
November 2017

Protective effects of ethanol extracts of Artemisia asiatica Nakai ex Pamp. on ageing-induced deterioration in mouse oocyte quality.

Zygote 2017 Aug 21;25(4):472-479. Epub 2017 Jun 21.

Department of Genetic Engineering,College of Biotechnology and Bioengineering,Sungkyunkwan University,Suwon,Korea.

Following ovulation, oocytes undergo a time-dependent deterioration in quality referred to as post-ovulatory ageing. Although various factors influence the post-ovulatory ageing of oocytes, oxidative stress is a key factor involved in deterioration of oocyte quality. Artemisia asiatica Nakai ex Pamp. has been widely used in East Asia as a food ingredient and traditional medicine for the treatment of inflammation, cancer, and microbial infections. Recent studies have shown that A. asiatica exhibits antioxidative effects. In this study, we investigated whether A. asiatica has the potential to attenuate deterioration in oocyte quality during post-ovulatory ageing. Freshly ovulated mouse oocytes were cultured with 0, 50, 100 or 200 μg/ml ethanol extracts of A. asiatica Nakai ex Pamp. After culture for up to 24 h, various ageing-induced oocyte abnormalities, including morphological changes, reactive oxygen species (ROS) accumulation, apoptosis, chromosome and spindle defects, and mitochondrial aggregation were determined. Treatment of oocytes with A. asiatica extracts reduced ageing-induced morphological changes. Moreover, A. asiatica extracts decreased ROS generation and the onset of apoptosis by preventing elevation of the Bax/Bcl-2 expression ratio during post-ovulatory ageing. Furthermore, A. asiatica extracts attenuated the ageing-induced abnormalities including spindle defects, chromosome misalignment and mitochondrial aggregation. Our results demonstrate that A. asiatica can relieve deterioration in oocyte quality and delay the onset of apoptosis during post-ovulatory ageing.
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http://dx.doi.org/10.1017/S0967199417000296DOI Listing
August 2017

Peroxiredoxins are required for spindle assembly, chromosome organization, and polarization in mouse oocytes.

Biochem Biophys Res Commun 2017 07 25;489(2):193-199. Epub 2017 May 25.

Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, South Korea. Electronic address:

Peroxiredoxins (Prxs) are highly conserved antioxidant enzymes and are implicated in multiple biological processes; however, their function in oocyte meiosis has not been studied. Here we show that inhibition of Prx I and II results in spindle defects, chromosome disorganization, and impaired polarization in mouse oocytes. Prx I was specifically localized at the spindle, whereas Prx II was enriched at the oocyte cortex and chromosomes. Inhibition of Prx activity with conoidin A disturbed assembly of the microtubule organizing center (MTOC) through Aurora A regulation, leading to defects in spindle formation. Moreover, conoidin A impaired actin filament and cortical granule (CG) distribution, disrupting actin cap and CG formation, respectively. Conoidin A also increased DNA damage without significantly increasing reactive oxygen species (ROS) levels, suggesting that the effects of conoidin A on meiotic maturation are not likely associated with ROS scavenging pathways. Therefore, our data suggest that Prxs are required for spindle assembly, chromosome organization, and polarization during meiotic maturation.
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http://dx.doi.org/10.1016/j.bbrc.2017.05.127DOI Listing
July 2017

Filamin A is required for spindle migration and asymmetric division in mouse oocytes.

FASEB J 2017 08 9;31(8):3677-3688. Epub 2017 May 9.

Department of Animal Sciences, Chungbuk National University, Cheongju, South Korea;

Dynamic changes in the actin network are crucial for the cortical migration of spindles and establishment of polarity, to ensure asymmetric division during meiotic maturation. In this study, filamin A (FLNA) was found to be an essential actin regulator that controlled spindle migration and asymmetric division during oocyte meiosis. FLNA was localized in the cytoplasm and enriched at the cortex and near the chromosomes. Knockdown of FLNA impaired meiotic asymmetric division and spindle migration with a decrease in the amount of cytoplasmic actin mesh and cortical actin levels. Moreover, FLNA knockdown reduced the phosphorylation of cofilin and Rho kinase (ROCK) near the spindle. Similar phenotypes, such as decreased filament actin levels, impaired spindle migration and polar body extrusion, were observed when active cofilin (S3A) was overexpressed or ROCK was inhibited. Notably, we found that FLNA and ROCK interacted directly in mouse oocytes. Taken together, our results show that FLNA plays crucial roles in asymmetric division during meiotic maturation by regulating ROCK-cofilin-mediated actin reorganization.-Wang, H., Guo J., Lin, Z., Namgoong, S., Oh, J. S., Kim, N.-H. Filamin A is required for spindle migration and asymmetric division in mouse oocytes.
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http://dx.doi.org/10.1096/fj.201700056RDOI Listing
August 2017

TCTP regulates spindle assembly during postovulatory aging and prevents deterioration in mouse oocyte quality.

Biochim Biophys Acta Mol Cell Res 2017 Jul 2;1864(7):1328-1334. Epub 2017 May 2.

Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address:

If no fertilization occurs for a prolonged time following ovulation, oocytes experience a time-dependent deterioration in quality both in vivo and in vitro due to processes called postovulatory aging. Because the postovulatory aging of oocytes has marked detrimental effects on embryo development and offspring, many efforts have been made to unveil the underlying mechanisms. Here we showed that translationally controlled tumor protein (TCTP) regulates spindle assembly during postovulatory aging and prevents deterioration in mouse oocyte quality. Spindle dynamics decreased with reduced TCTP level during aging of mouse oocytes. Knockdown of TCTP accelerated the reduction of spindle dynamics, accompanying with aging-related deterioration of oocyte quality. Conversely, overexpression of TCTP prevented aging-associated decline of spindle dynamics. Moreover, the aging-related abnormalities in oocytes were rescued after TCTP overexpression, thereby improving fertilization competency and subsequent embryo development. Therefore, our results demonstrate that TCTP-mediated spindle dynamics play a key role in maintaining oocyte quality during postovulatory aging and overexpression of TCTP is sufficient to prevent aging-associated abnormalities in mouse oocytes.
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http://dx.doi.org/10.1016/j.bbamcr.2017.05.002DOI Listing
July 2017

Quercetin delays postovulatory aging of mouse oocytes by regulating SIRT expression and MPF activity.

Oncotarget 2017 Jun;8(24):38631-38641

Department of Animal Sciences, Chungbuk National University, Cheongju, Korea.

If no fertilization occurs at an appropriate time after ovulation, oocyte quality deteriorates rapidly as a process called postovulatory aging. Because the postovulatory aging of oocytes has detrimental effects on embryo development and offspring, many efforts have been made to prevent oocyte aging. Here we showed that quercetin prevented the decline in oocyte quality during postovulatory aging of oocytes. Quercetin treatment reduced aging-induced morphological changes and reactive oxygen species accumulation. Moreover, quercetin attenuated the aging-associated abnormalities in spindle organization and mitochondrial distribution, preventing decrease of SIRT expression and histone methylation. Quercetin also ameliorated the decrease in maturation-promoting factor activity and the onset of apoptosis during postovulatory aging. Furthermore, quercetin treatment during postovulatory aging improves early embryo development. Our results demonstrate that quercetin relieves deterioration in oocyte quality and improves subsequent embryo development.
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http://dx.doi.org/10.18632/oncotarget.16219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5503559PMC
June 2017

Hydrolysis of Hyaluronic Acid in Lymphedematous Tissue Alleviates Fibrogenesis via T1 Cell-Mediated Cytokine Expression.

Sci Rep 2017 02 24;7(1):35. Epub 2017 Feb 24.

Department of Genetic Engineering, Sungkyunkwan University, Suwon, 16419, Republic of Korea.

Although surgery and radiation are beneficial for treating cancer, they can also lead to malfunctions of the lymphatic system such as secondary lymphedema. This abnormality of the lymphatic system is characterized by severe swelling, adipogenesis, inflammation, and fibrosis in the lymphedematous region. Moreover, the proliferation of fibrotic tissue in the lymphedematous region generates edema that is no longer spontaneously reversible. No treatment for fibrosis has been validated in patients with lymphedema. In our efforts to develop a therapeutic agent for lymphedema fibrosis, we used a newly established mouse hind limb model. Previous studies have demonstrated that hyaluronic acid accumulates in the lymphedematous region. Thus, we challenged mice with of hyaluronidase (HYAL), with the aim of reducing fibrogenesis. After subcutaneous injections in the lymphedematous mouse leg every two days, the volume of lymphedema had reduced significantly by 7 days post-operation. Histochemical analysis indicated that collagen accumulation and myofibroblast differentiation were decreased in epidermal tissues after HYAL injection. Moreover, it was associated with upregulation of interferon-gamma, increased numbers of Th1 cells, and downregulation of interleukin-4 and interleukin-6 in the lymphedematous region and spleen. These results indicate that hydrolysis of hyaluronic acid can boost an anti-fibrotic immune response in the mouse lymphedema model.
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http://dx.doi.org/10.1038/s41598-017-00085-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5428353PMC
February 2017

Inhibition of CDK7 bypasses spindle assembly checkpoint via premature cyclin B degradation during oocyte meiosis.

Biochim Biophys Acta 2016 12;1863(12):2993-3000

Department of Animal Sciences, Chungbuk National University, Cheongju, Republic of Korea. Electronic address:

To ensure accurate chromosome segregation, the spindle assembly checkpoint (SAC) delays anaphase onset by preventing the premature activation of anaphase-promoting complex/cyclosome (APC/C) until all kinetochores are attached to the spindle. Although an escape from mitosis in the presence of unsatisfied SAC has been shown in several cancer cells, it has not been reported in oocyte meiosis. Here, we show that CDK7 activity is required to prevent a bypass of SAC during meiosis I in mouse oocytes. Inhibition of CDK7 using THZ1 accelerated the first meiosis, leading to chromosome misalignment, lag of chromosomes during chromosome segregation, and a high incidence of aneuploidy. Notably, this acceleration occurred in the presence of SAC proteins including Mad2 and Bub3 at the kinetochores. However, inhibition of APC/C-mediated cyclin B degradation blocked the THZ1-induced premature polar body extrusion. Moreover, chromosomal defects mediated by THZ1 were rescued when anaphase onset was delayed. Collectively, our results show that CDK7 activity is required to prevent premature anaphase onset by suppressing the bypass of SAC, thus ensuring chromosome alignment and proper segregation. These findings reveal new roles of CDK7 in the regulation of meiosis in mammalian oocytes.
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http://dx.doi.org/10.1016/j.bbamcr.2016.09.020DOI Listing
December 2016

Erratum to: Attenuation of Aβ toxicity by promotion of mitochondrial fusion in neuroblastoma cells by liquiritigenin.

Arch Pharm Res 2016 Sep;39(9):1337

Graduate School of East-West Medical Science, Kyung Hee University, Yongin-Si, Gyeonggi-Do, 17104, Republic of Korea.

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http://dx.doi.org/10.1007/s12272-016-0830-9DOI Listing
September 2016

Attenuation of Aβ toxicity by promotion of mitochondrial fusion in neuroblastoma cells by liquiritigenin.

Arch Pharm Res 2016 Aug 12;39(8):1137-43. Epub 2016 Aug 12.

Graduate School of East-West Medical Science, Kyung Hee University, Yongin-Si, Gyeonggi-Do, 17104, Republic of Korea.

Mitochondrial dynamics control mitochondrial morphology and function, and aberrations in these are associated with various neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. To identify novel regulators of mitochondrial dynamics, we screened a phytochemical library and identified liquiritigenin as a potent inducer of mitochondrial fusion. Treatment with liquiritigenin induced an elongated mitochondrial morphology in SK-N-MC cells. In addition, liquiritigenin rescued mitochondrial fragmentation induced by knockout of mitochondrial fusion mediators such as Mfn1, Mfn2, and Opa1. Furthermore, we found that treatment with liquiritigenin notably inhibited mitochondrial fragmentation and cytotoxicity induced by Aβ in SK-N-MC cells.
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http://dx.doi.org/10.1007/s12272-016-0780-2DOI Listing
August 2016

Eccentric localization of catalase to protect chromosomes from oxidative damages during meiotic maturation in mouse oocytes.

Histochem Cell Biol 2016 Sep 9;146(3):281-8. Epub 2016 May 9.

Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do, 440-746, Korea.

The maintenance of genomic integrity and stability is essential for the survival of every organism. Unfortunately, DNA is vulnerable to attack by a variety of damaging agents. Oxidative stress is a major cause of DNA damage because reactive oxygen species (ROS) are produced as by-products of normal cellular metabolism. Cells have developed eloquent antioxidant defense systems to protect themselves from oxidative damage along with aerobic metabolism. Here, we show that catalase (CAT) is present in mouse oocytes to protect the genome from oxidative damage during meiotic maturation. CAT was expressed in the nucleus to form unique vesicular structures. However, after nuclear envelope breakdown, CAT was redistributed in the cytoplasm with particular focus at the chromosomes. Inhibition of CAT activity increased endogenous ROS levels, but did not perturb meiotic maturation. In addition, CAT inhibition produced chromosomal defects, including chromosome misalignment and DNA damage. Therefore, our data suggest that CAT is required not only to scavenge ROS, but also to protect DNA from oxidative damage during meiotic maturation in mouse oocytes.
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http://dx.doi.org/10.1007/s00418-016-1446-3DOI Listing
September 2016

Beclin-1 knockdown shows abscission failure but not autophagy defect during oocyte meiotic maturation.

Cell Cycle 2016 06 5;15(12):1611-9. Epub 2016 May 5.

a Department of Genetic Engineering , College of Biotechnology and Bioengineering, Sungkyunkwan University , Suwon , Gyeonggi-do , Korea.

Cytokinesis is the final step in cell division that results in the separation of a parent cell into daughter cells. Unlike somatic cells that undergo symmetric division, meiotic division is highly asymmetric, allowing the preservation of maternal resources for embryo development. Beclin-1/BECN1, the mammalian homolog of yeast Atg6, is a key molecule of autophagy. As part of a class III phosphatidylinositol 3-kinase (PI3K-III) complex, BECN1 initiates autophagosome formation by coordinating membrane trafficking. However, emerging evidence suggests that BECN1 regulates chromosome segregation and cytokinesis during mitosis. Thus, we investigated the function of BECN1 during oocyte meiotic maturation. BECN1 was widely distributed during meiotic maturation forming small vesicles. Interestingly, BECN1 is also detected at the midbody ring during cytokinesis. Depletion of BECN1 impaired the cytokinetic abscission, perturbing the recruitment of ZFYVE26 at the midbody. Similar phenotypes were observed when PI3K-III activity was inhibited. However, inhibition of autophagy by depleting Atg14L did not disturb meiotic maturation. Therefore, our results not only demonstrate that BECN1 as a PI3K-III component is essential for cytokinesis, but also suggest that BECN1 is not associated with autophagy pathway in mouse oocytes.
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http://dx.doi.org/10.1080/15384101.2016.1181235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934058PMC
June 2016

TCTP regulates spindle microtubule dynamics by stabilizing polar microtubules during mouse oocyte meiosis.

Biochim Biophys Acta 2016 Apr 21;1863(4):630-7. Epub 2016 Jan 21.

Department of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Republic of Korea. Electronic address:

Dynamic changes in spindle structure and function are essential for maintaining genomic integrity during the cell cycle. Spindle dynamics are highly dependent on several microtubule-associated proteins that coordinate the dynamic behavior of microtubules, including microtubule assembly, stability and organization. Here, we show that translationally controlled tumor protein (TCTP) is a novel microtubule-associated protein that regulates spindle dynamics during meiotic maturation. TCTP was expressed and widely distributed in the cytoplasm with strong enrichment at the spindle microtubules during meiosis. TCTP was found to be phosphorylated during meiotic maturation, and was exclusively localized to the spindle poles. Knockdown of TCTP impaired spindle organization without affecting chromosome alignment. These spindle defects were mostly due to the destabilization of the polar microtubules. However, the stability of kinetochore microtubules attached to chromosomes was not affected by TCTP knockdown. Overexpression of a nonphosphorylable mutant of TCTP disturbed meiotic maturation, stabilizing the spindle microtubules. In addition, Plk1 was decreased by TCTP knockdown. Taken together, our results demonstrate that TCTP is a microtubule-associating protein required to regulate spindle microtubule dynamics during meiotic maturation in mouse oocytes.
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http://dx.doi.org/10.1016/j.bbamcr.2016.01.012DOI Listing
April 2016

STAT3-survivin signaling mediates a poor response to radiotherapy in HER2-positive breast cancers.

Oncotarget 2016 Feb;7(6):7055-65

Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.

Although radiotherapy resistance is associated with locoregional recurrence and distant metastasis in breast cancers, clinically relevant molecular markers and critical signaling pathways of radioresistant breast cancer are yet to be defined. Herein, we show that HER2-STAT3-survivin regulation is associated with radiotherapy resistance in HER2-positive breast cancers. Depletion of HER2 by siRNA sensitized HER2-positive breast cancer cells to irradiation by decreasing STAT3 activity and survivin, a STAT3 target gene, expression in HER2-positive breast cancer cells. Furthermore, inhibition of STAT3 activation or depletion of survivin also sensitized HER2-positive breast cancer cells to irradiation, suggesting that the HER2-STAT3-survivin axis is a key pathway in radiotherapy resistance of HER2-positive breast cancer cells. In addition, our clinical analysis demonstrated the association between HER2-positive breast cancers and radiotherapy resistance. Notably, we found that increased expression of phosphorylated STAT3, STAT3, and survivin correlated with a poor response to radiotherapy in HER2-positive breast cancer tissues. These findings suggest that the HER2-STAT3-survivin axis might serve as a predictive marker and therapeutic target to overcome radiotherapy resistance in HER2-positive breast cancers.
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http://dx.doi.org/10.18632/oncotarget.6855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4872768PMC
February 2016

Proton Irradiation Sensitizes Radioresistant Non-small Cell Lung Cancer Cells by Modulating Epidermal Growth Factor Receptor-mediated DNA Repair.

Anticancer Res 2016 Jan;36(1):205-12

Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea

Although proton radiotherapy is effective in treating various types of cancer, little is known on the biological responses triggered by proton irradiation. In the present study, we investigated protein profiles following proton irradiation of non-small cell lung cancer (NSCLC) cells and defined the role of proton-induced epidermal growth factor receptor (EGFR) expression in NSCLC cells. We found that proton irradiation more effectively sensitized NSCLC cells than gamma irradiation did. The expression profiles of radiosensitive and radioresistant NSCLC cells following proton and gamma irradiation were examined using antibody arrays. With regard to proteins, expression of EGFR was the most highly induced by proton irradiation. In addition, we found that EGFR inhibition with gefinitib significantly increased the radiosensitivity of NSCLC cells, and that increased radiosensitivity due to gefinitib was mediated by the suppression of DNA repair in radioresistant NSCLC cells. Thus, our data provide the first evidence that proton irradiation sensitizes radioresistant NSCLC cancer cells by modulating EGFR-mediated DNA repair.
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January 2016