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Ahnak depletion accelerates liver regeneration by modulating the TGF-β/Smad signaling pathway
Insook Yang,Yeri Son,Jae Hoon Shin,Il Yong Kim,Je Kyung Seong 생화학분자생물학회 2022 BMB Reports Vol.55 No.8
Ahnak, a large protein first identified as an inhibitor of TGF-βsignaling in human neuroblastoma, was recently shown to promoteTGF-β in some cancers. The TGF-β signaling pathway regulatescell growth, various biological functions, and cancergrowth and metastasis. In this study, we used Ahnak knockout(KO) mice that underwent a 70% partial hepatectomy (PH) toinvestigate the function of Ahnak in TGF-β signaling during liverregeneration. At the indicated time points after PH, we analyzedthe mRNA and protein expression of the TGF -β/Smad signalingpathway and cell cycle-related factors, evaluated the cell cyclethrough proliferating cell nuclear antigen (PCNA) immunostaining,analyzed the mitotic index by hematoxylin and eosinstaining. We also measured the ratio of liver tissue weight tobody weight. Activation of TGF-β signaling was confirmed byanalyzing the levels of phospho-Smad 2 and 3 in the liver atthe indicated time points after PH and was lower in Ahnak KOmice than in WT mice. The expression levels of cyclin B1, D1,and E1; proteins in the Rb/E2F transcriptional pathway, whichregulates the cell cycle; and the numbers of PCNA-positive cellswere increased in Ahnak KO mice and showed tendencies oppositethat of TGF-β expression. During postoperative regeneration,the liver weight to body weight ratio tended to increasefaster in Ahnak KO mice. However, 7 days after PH, both groupsof mice showed similar rates of regeneration, following whichtheir active regeneration stopped. Analysis of hepatocytes undergoingmitosis showed that there were more mitotic cells inAhnak KO mice, consistent with the weight ratio. Our findingssuggest that Ahnak enhances TGF-β signaling during postoperativeliver regeneration, resulting in cell cycle disruption; thishighlights a novel role of Ahnak in liver regeneration. Theseresults provide new insight into liver regeneration and potentialtreatment targets for liver diseases that require surgicaltreatment.
O- and N-Methyltransferases in benzylisoquinoline alkaloid producing plants
Lee Seungki,Park Nam-Il,Park Yeri,Park Kyong-Cheul,Kim Eun Sil,Son Youn Kyoung,Choi Beom-Soon,Kim Nam-Soo,Choi Ik-Young 한국유전학회 2024 Genes & Genomics Vol.46 No.3
Background Secondary metabolites such as benzylisoquinoline alkaloids (BIA) have attracted considerable attention because of their pharmacological properties and potential therapeutic applications. Methyltransferases (MTs) can add methyl groups to alkaloid molecules, altering their physicochemical properties and bioactivity, stability, solubility, and recognition by other cellular components. Five types of O-methyltransferases and two types of N-methyltransferases are involved in BIA biosynthesis. Objective Since MTs may be the source for the discovery and development of novel biomedical, agricultural, and industrial compounds, we performed extensive molecular and phylogenetic analyses of O- and N-methyltransferases in BIA-producing plants. Methods MTs involved in BIA biosynthesis were isolated from transcriptomes of Berberis koreana and Caulophyllum robustum. We also mined the methyltransferases of Coptis japonica, Papaver somniferum, and Nelumbo nucifera from the National Center for Biotechnology Information protein database. Then, we analyzed the functional motifs and phylogenetic analysis. Result We mined 42 O-methyltransferases and 8 N-methyltransferases from the five BIA-producing plants. Functional motifs for S-adenosyl-L-methionine-dependent methyltransferases were retained in most methyltransferases, except for the three O-methyltransferases from N. nucifera. Phylogenetic analysis revealed that the methyltransferases were grouped into four clades, I, II, III and IV. The clustering patterns in the phylogenetic analysis suggested a monophyletic origin of methyltransferases and gene duplication within species. The coexistence of different O-methyltransferases in the deep branch subclade might support some cases of substrate promiscuity. Conclusions Methyltransferases may be a source for the discovery and development of novel biomedical, agricultural, and industrial compounds. Our results contribute to further understanding of their structure and reaction mechanisms, which will require future functional studies. Background Secondary metabolites such as benzylisoquinoline alkaloids (BIA) have attracted considerable attention because of their pharmacological properties and potential therapeutic applications. Methyltransferases (MTs) can add methyl groups to alkaloid molecules, altering their physicochemical properties and bioactivity, stability, solubility, and recognition by other cellular components. Five types of O-methyltransferases and two types of N-methyltransferases are involved in BIA biosynthesis. Objective Since MTs may be the source for the discovery and development of novel biomedical, agricultural, and industrial compounds, we performed extensive molecular and phylogenetic analyses of O- and N-methyltransferases in BIA-producing plants. Methods MTs involved in BIA biosynthesis were isolated from transcriptomes of Berberis koreana and Caulophyllum robustum. We also mined the methyltransferases of Coptis japonica, Papaver somniferum, and Nelumbo nucifera from the National Center for Biotechnology Information protein database. Then, we analyzed the functional motifs and phylogenetic analysis. Result We mined 42 O-methyltransferases and 8 N-methyltransferases from the five BIA-producing plants. Functional motifs for S-adenosyl-L-methionine-dependent methyltransferases were retained in most methyltransferases, except for the three O-methyltransferases from N. nucifera. Phylogenetic analysis revealed that the methyltransferases were grouped into four clades, I, II, III and IV. The clustering patterns in the phylogenetic analysis suggested a monophyletic origin of methyltransferases and gene duplication within species. The coexistence of different O-methyltransferases in the deep branch subclade might support some cases of substrate promiscuity. Conclusions Methyltransferases may be a source for the discovery and development of novel biomedical, agricultural, and industrial compounds. Our results contribute to further understanding of their structure and reaction mechanisms, which will require future functional studies.
고려엉겅퀴와 큰엉겅퀴의 모상근 유도 및 methyl jasmonate 처리에 따른 HPLC 패턴 변화
Tae Gyu Yi,Jong Dai Son,Yeri Park,Byung Hun Um,Nam Il Park 한국약용작물학회 2017 한국약용작물학술대회 발표집 Vol.2017 No.05
Background : Cirsium plants have been used for perennial edible plants and grow wild in the mountainous regions of Korea, including Cirsium setidens and C. pendulum. In particular, C. setidens is commonly called 'gondre', and it has been used medicinally for diseases such as hematuria, hepatitis and hypertension. Hairy roots cultivation can be used as a method for increasing production through mass culture of medicinal plants, and elicitors such as methyl jasmonate (MeJa) can be treated to increase the content of certain useful ingredients. In this study, the hairy root was derived from the leaf tissues of C. setidens and C. pendulum, and the HPLC pattern was compared by MeJa treatment. Methods and Results : Agrobacterium rhizogenes R1000 was used to induce hairy roots in 1/2× MS medium. In addition, the hairy roots was treated with MeJa for different time (0, 1, 2, 5, 10, 24, 48, 72 h) and with various concentrations (0, 10, 50, 100, 200, 300 μM). The HPLC pattern changes were analyzed by on-line HPLC-ABTS. Four new peaks were observed in both Cirsium setidens and C. pendulum hairy roots, all of which showed antioxidant activity. In the case of C. pendulum, chlorogenic acid content was about 4 times higher than that of leaves. These peaks, including chlorogenic acid, were all affected by MeJa treatment. Conclusion : Four peaks were detected in the hairy roots of C. setidens and C. pendulum not in the leaves, and they were confirmed to be affected by the treatment of MeJa. It is necessary to clarify the structure through the subsequent compound separation.
Ahnak gene deficiency promotes type II pneumocyte hyperplasia and lung tumor development in mice
Jun Won Park,Il Yong Kim,Dong Su Kyeong,Ji Won Choi,Hee Jung Lim,Jae Hoon Shin,Yo Na Kim,Seo Hyun Lee,Yeri Son,Mira Sohn,Jong Kyu Woo,Joseph H. Jeong,Cheolju Lee,Yun Soo Bae,Je Kyung Seong 한국실험동물학회 2018 한국실험동물학회 학술발표대회 논문집 Vol.2018 No.7
AHNAK Loss in Mice Promotes Type II Pneumocyte Hyperplasia and Lung Tumor Development
Park, Jun Won,Kim, Il Yong,Choi, Ji Won,Lim, Hee Jung,Shin, Jae Hoon,Kim, Yo Na,Lee, Seo Hyun,Son, Yeri,Sohn, Mira,Woo, Jong Kyu,Jeong, Joseph H.,Lee, Cheolju,Bae, Yun Soo,Seong, Je Kyung American Association for Cancer Research 2018 Molecular Cancer Research Vol.16 No.8
<P>AHNAK is known to be a tumor suppressor in breast cancer due to its ability to activate the TGFβ signaling pathway. However, the role of AHNAK in lung tumor development and progression remains unknown. Here, the Ahnak gene was disrupted to determine its effect on lung tumorigenesis and the mechanism by which it triggers lung tumor development was investigated. First, AHNAK protein expression was determined to be decreased in human lung adenocarcinomas compared with matched nonneoplastic lung tissues. Then, Ahnak<I><SUP>−/−</SUP></I> mice were used to investigate the role of AHNAK in pulmonary tumorigenesis. Ahnak<I><SUP>−/−</SUP></I> mice showed increased lung volume and thicker alveolar walls with type II pneumocyte hyperplasia. Most importantly, approximately 20% of aged Ahnak<I><SUP>−/−</SUP></I> mice developed lung tumors, and Ahnak<I><SUP>−/−</SUP></I> mice were more susceptible to urethane-induced pulmonary carcinogenesis than wild-type mice. Mechanistically, Ahnak deficiency promotes the cell growth of lung epithelial cells by suppressing the TGFβ signaling pathway. In addition, increased numbers of M2-like alveolar macrophages (AM) were observed in Ahnak<I><SUP>−/−</SUP></I> lungs, and the depletion of AMs in Ahnak<I><SUP>−/−</SUP></I> lungs alleviated lung hyperplastic lesions, suggesting that M2-like AMs promoted the progression of lung hyperplastic lesions in Ahnak-null mice. Collectively, AHNAK suppresses type II pneumocyte proliferation and inhibits tumor-promoting M2 alternative activation of macrophages in mouse lung tissue. These results suggest that AHNAK functions as a novel tumor suppressor in lung cancer.</P><P><B>Implications:</B> The tumor suppressor function of AHNAK, in murine lungs, occurs by suppressing alveolar epithelial cell proliferation and modulating lung microenvironment. <I>Mol Cancer Res; 16(8); 1287–98. ©2018 AACR</I>.</P>