がん細胞特異的傷害法におけるがん細胞特異的なE2F活性の有用性の検討

関西学院大

The Key Role of E2F in Tumor Suppression through Specific Regulation of Tumor Suppressor Genes in Response to Oncogenic Changes

E2F, the principal target of the tumor suppressor pRB, plays crucial roles in tumor suppression. Upon dysfunction of pRB, E2F activates tumor suppressor genes such as ARF, an upstream activator of the tumor suppressor p53, resulting in the induction of apoptosis and tumor suppression. The E2F activity that activates the tumor suppressor genes is detected only in cancer cells and not in normal growing cells. The E2F activity can drive selective suicide gene expression and induce apoptosis specifically in cancer cells. Thus, the E2F activity provides a beneficial tool to specifically target cancer cells in cancer treatment

Pillar[6]arene acts as a biosensor for quantitative detection of a vitamin metabolite in crude biological samples

ビタミン代謝物を迅速定量できる超分子バイオセンサーを開発. 京都大学プレスリリース. 2020-12-09.Metabolic syndrome is associated with obesity, hypertension, and dyslipidemia, and increased cardiovascular risk. Therefore, quick and accurate measurements of specific metabolites are critical for diagnosis; however, detection methods are limited. Here we describe the synthesis of pillar[n]arenes to target 1-methylnicotinamide (1-MNA), which is one metabolite of vitamin B3 (nicotinamide) produced by the cancer-associated nicotinamide N-methyltransferase (NNMT). We found that water-soluble pillar[5]arene (P5A) forms host–guest complexes with both 1-MNA and nicotinamide, and water-soluble pillar[6]arene (P6A) selectively binds to 1-MNA at the micromolar level. P6A can be used as a “turn-off sensor” by photoinduced electron transfer (detection limit is 4.38 × 10−6 M). In our cell-free reaction, P6A is used to quantitatively monitor the activity of NNMT. Moreover, studies using NNMT-deficient mice reveal that P6A exclusively binds to 1-MNA in crude urinary samples. Our findings demonstrate that P6A can be used as a biosensor to quantify 1-MNA in crude biological samples

Correspondance de Frédéric II avec Louise-Dorothée de Saxe-Gotha (1740-1767)

Voici éditées pour la première fois intégralement les lettres échangées par Frédéric II et la duchesse de Saxe-Gotha, à partir des manuscrits conservés à Berlin et à Gotha. On y découvre comment Louise-Dorothée a cherché à aider Frédéric II par ses renseignements, ses interventions politiques ou ses démarches en faveur de la paix. <br/> Cette femme d'action était aussi une femme cultivée, qui fit connaître à son correspondant des ouvrages de Hume, Voltaire, Rousseau, Boulanger, ainsi que la <em>Correspondance littéraire</em> de Grimm. Le roi, souvent caustique dans ses jugements, lui adressa, de son côté, poèmes et œuvres satiriques. Il s'ensuit, à côté d'éloges sincères, des discussions philosophiques où la duchesse n'hésite pas à défendre parfois, sur la Providence ou la survie, des opinions opposées à celles de son royal correspondant. Leurs lettres, de plus en plus riches, révèlent en outre une admiration réciproque, une estime, une amitié qui vont croissant.<br/><br/> Table des illustrations<br/> Remerciements<br/> Avertissement et principes de cette édition<br/> Abréviations<br/> Introduction<br/> 1. Paradoxe de cet échange épistolaire<br/> 2. Raisons profondes de cet échange épistolaire<br/> 3. Les premières lettres: recrues et tutelles<br/> 4. Importance historique de cette correspondance: la guerre de Sept ans<br/> 5. Intérêt philosophique et littéraire de ces lettres<br/> 6. Les rapports de place<br/> 7. La langue et le style<br/> 8. Manuscrits et éditions<br/> Correspondance <br/> Annexes<br/> I. Manuscrits<br/> II. Imprimés<br/> Bibliographie<br/> Index<br/

ゲノム編集技術を用いた白血病幹細胞の分化制御に関わる因子の同定と機能解析

急性骨髄性白血病（AML）は、造血幹・前駆細胞から生じる悪性腫瘍で、異常増殖と分化不全を特徴とする。白血病幹細胞の未分化性維持に必須な転写因子FOXOの機能解析の過程で、分化が解糖系をはじめとした代謝制御と深く関連していることを見いだした。本研究では、FOXO下流の代謝関連遺伝子に着目し、未分化維持因子の探索を進めるとともに、生体に存在するすべての代謝酵素、トランスポーターを対象にCRISPR機能的スクリーニングを行い、白血病幹細胞の未分化性に寄与する代謝制御機構を解析した。未分化維持に寄与する代謝酵素を複数同定した。また、その阻害剤は白血病細胞特異的に抗増殖作用を示した。Acute myeloid leukemia (AML) is malignant disease characterized by abnormal proliferation and differentiation blockade. We have found that metabolic reprograming including glycolysis are related with differentiation in the process of research into FOXO’s function. In this project, regulators of differentiation blockade are explored from FOXO target genes related with metabolism or all metabolic enzymes and transporters using CRISPR Cas9 screening. We have found that some metabolic enzymes play pivotal role in differentiation blockade. Moreover, the inhibitor represses proliferation of leukemia specifically.研究課題/領域番号:19K17824, 研究期間(年度):2019-04-01 - 2021-03-31出典：「ゲノム編集技術を用いた白血病幹細胞の分化制御に関わる因子の同定と機能解析」研究成果報告書　課題番号19K17824（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-19K17824/19K17824seika/）を加工して作

Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation

Abstract Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation