Microscopic dissection of the process of stress granule assembly

AbstractStress granules (SGs) are mRNA triage sites that are formed in response to a variety of cellular stress. To study how SGs bring about the massive spatial compartmentalization, we monitored the localization of various RNA-binding proteins (RBPs) targeted to SGs upon exposure to stress. We discovered that concomitant with the onset of eIF2α phosphorylation, RBPs accumulate locally in the cytoplasm, which leads to increased inter-molecular interactions and the formation of robustly detergent-resistant foci. Subsequently, microtubules (MTs) mediate 1) the ordered spatial organization of SGs and 2) the recruitment of a set of nuclear-localized SG components to the cytoplasm. Meanwhile, MTs did not appear to be required for the maintenance of SG distribution after its assembly. Our data suggest that the process of SG formation is composed of MT-independent and -dependent pathways, which take place sequentially during stress response

Small mitochondrial ARF (smARF) is located in both the nucleus and cytoplasm, induces cell death, and activates p53 in mouse fibroblasts

AbstractThe ARF transcript produces two proteins, the full-length ARF, p19ARF, and a short mitochondrial version, smARF. To explore the functional difference between the two, we generated GFP-fused expression vectors for each protein and introduced them into NIH3T3 murine fibroblasts, which sustains a global deletion in the INK4a locus but contains a functional p53 gene. GFP-p19ARF was located within the nucleolus as previously reported, whereas GFP-smARF was detected mainly in the nucleoplasm. GFP-smARF induced cell death although to a slightly lesser extent than p19ARF. GFP-smARF stabilized p53 thereby inducing expression of the target genes, MDM2 and p21. We suggest that smARF has functions other than mitochondria-mediated autophagy, and induces p53 expression and cell death via a novel mechanism

複数異種移植マウスモデルにおけるPentagamavunone-1の膵臓癌に対する単剤および併用療法としての前臨床評価

We previously reported that pentagamavunone-1 (PGV-1) effectively inhibited cell proliferation in many types of human tumors, including pancreatic cancer, by inducing M phase (prometaphase) arrest, senescence, and apoptosis with few side effects. However, a detailed evaluation of the effects of PGV-1 on pancreatic cancer cells in an in vivo setting has not yet been conducted. The present study investigated the potential efficacy of PGV-1 as both monotherapy and combination therapy for pancreatic cancer using multiple xenograft mouse assays. A cell-line derived xenograft model (CDX-M) with pancreatic cancer cell line and a patient-derived xenograft mouse model (PDX-M) using resected pancreatic cancer samples without neoadjuvant chemotherapy were established in both heterotopic and orthotopic manners. PGV-1 effectively suppressed tumor formation at the heterotopic and orthotopic sites in CDX-M than in untreated mice. Combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation than monotherapy with PGV-1 or gemcitabine when administered after tumor formation. Monotherapy with PGV-1 or gemcitabine less effectively suppressed tumor formation in PDX-M than in CDX-M, whereas combination therapy with PGV-1 and gemcitabine more effectively suppressed tumor formation. PGV-1 as monotherapy and combination therapy with gemcitabine effectively inhibited tumor formation and has potential as an anticancer candidate for pancreatic cancer.権利情報：© The Author(s) 2022. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/

半導体量子ドットを用いた単一電子スピン量子ビットの高速電気制御

学位の種別:課程博士University of Tokyo(東京大学