The Quiescent Cellular State is Arf/p53-Dependent and Associated with H2AX Downregulation and Genome Stability

Cancer is a disease associated with genomic instability and mutations. Excluding some tumors with specific chromosomal translocations, most cancers that develop at an advanced age are characterized by either chromosomal or microsatellite instability. However, it is still unclear how genomic instability and mutations are generated during the process of cellular transformation and how the development of genomic instability contributes to cellular transformation. Recent studies of cellular regulation and tetraploidy development have provided insights into the factors triggering cellular transformation and the regulatory mechanisms that protect chromosomes from genomic instability

Spatial distribution of lipid headgroups and water molecules at membrane/water interfaces visualized by three-dimensional scanning force microscopy

At biological interfaces, flexible surface structures and mobile water interact with each other to present non-uniform three-dimensional (3D) distributions. In spite of their impact on biological functions, molecular-scale understanding of such phenomena has remained elusive. Here we show direct visualization of such interfacial structures with subnanometer-scale resolution by 3D scanning force microscopy (3D-SFM). We measured a 3D force distribution at an interface between a model biological membrane and buffer solution by scanning a sharp tip within the 3D interfacial space. We found that vertical cross sections of the 3D image taken along a specific lateral direction show characteristic molecular-scale contrasts tilted at 30° to the membrane surface. Detailed analysis of the 3D image reveals that the tilted contrast corresponds to the time-averaged conformation of fluctuating lipid headgroups. On the basis of the obtained results, we discuss the relationships among the hydration structure, headgroup fluctuation, molecular fluidity, and mechanical strength of the membrane. The results demonstrate that 3D-SFM is capable of visualizing averaged 3D distribution of fluctuating surface structures as well as that of mobile water (i.e., hydration structure) at interfaces between biological systems and water. © 2012 American Chemical Society

DNA Lesions Induced by Replication Stress Trigger Mitotic Aberration and Tetraploidy Development

During tumorigenesis, cells acquire immortality in association with the development of genomic instability. However, it is still elusive how genomic instability spontaneously generates during the process of tumorigenesis. Here, we show that precancerous DNA lesions induced by oncogene acceleration, which induce situations identical to the initial stages of cancer development, trigger tetraploidy/aneuploidy generation in association with mitotic aberration. Although oncogene acceleration primarily induces DNA replication stress and the resulting lesions in the S phase, these lesions are carried over into the M phase and cause cytokinesis failure and genomic instability. Unlike directly induced DNA double-strand breaks, DNA replication stress-associated lesions are cryptogenic and pass through cell-cycle checkpoints due to limited and ineffective activation of checkpoint factors. Furthermore, since damaged M-phase cells still progress in mitotic steps, these cells result in chromosomal mis-segregation, cytokinesis failure and the resulting tetraploidy generation. Thus, our results reveal a process of genomic instability generation triggered by precancerous DNA replication stress

Marbles from Tokushima Prefecture, used in the National Diet Building : Part 1: locality and geological framework

The quarries of marbles for the construction of the National Diet Building (Nagata-cho, Chiyodaku, Tokyo) were identified in Tokushima Prefecture. The geological setting and microfossil age of the marbles were studied. Seven brands, "Akebono", "Kito-ishi ", "Hototogisu", "Kamo-sarasa", "Awayuki ", "Kotajima" and "Shin-awayuki" were used in the House of Councilors and the Central part of the building. The "Akebono", used for the wall along the Councilor's Second Stairway, is Silurian limestone from the Hiakari-yama lenticular body of the Kurosegawa Tectonic Zone in the Koyama-daira area (Kisawa Village). The "Kito-ishi" from the Misago-yama area (Kisawa Village), used for the fireplace in the reception room of the Vice-president of the House of Councilors, is the limestone and greenstone breccia intercalated in the Upper Carboniferous alternation of chert and pelagic limestone in the Permian accretion terrene (Masaki Belt of the Kurosegawa Terrane). The "Hototogisu", used for the well-ornamented entrance gate of the Emperor's room "Gokyujo", is the Upper Triassic dolimitic limestone in the Late Jurassic-earliest Cretaceous accretion mélange of the South Chichibu Terrane (Tsunomine Subbelt) from the Arida area (Asebi-cho, Anan City). The "Kamo-sarasa", used for the inside wall of the central entrance of the building, is the Upper Triassic limestone with some green reticulation in Late Jurassic-earliest Cretaceous accretion mélange of the South Chichibu Terrane (Tsunomine Subbelt) from the Oji area (Kuwano-cho, Anan City). The "Awayuki", used for the lower part of the wall along the square in front of the Emperor's room, and the lower part of the wall around the assembly hall of the House of Councilors, presumed to be a kind of "Kamo-sarasa", is proved to be the Upper Triassic Megalodon limestone with hexacoral-bearing dark limestone blocks in the accretion mélange of the South Chichibu Terrane (Tsunomine Subbelt) from the Kurogo area (Kamo-cho, Anan City). The "Kotajima", used for the lower part of the wall along the passage of the second floor, and the wall along the "Kisha Kaidan" stairway, is proved to be the Upper Triassic limestone with reticulation of black cleavages in Late Jurassic-earliest Cretaceous accretion mélange of the South Chichibu Terrane (Tsunomine Subbelt) from the Higashibun area (Tsunomine-cho, Anan City). The "Shin-awayuki", used for the mosaic on the floor of the Central Hall and the lower part of the wall along the passage of the southern central part of the first floor, is the Upper Carboniferous limestone in Jurassic accretion mélange of the South Chichibu Belt (Hosono Subbelt) from the Izeki area (Takarada-cho, Anan City)

Immunosuppressant FK506 induces interleukin-6 production through the activation of transcription factor nuclear factor (NF)-κB implications for FK506 nephropathy

金沢大学がん研究所がん分子細胞制御FK506 is a powerful immunosuppressive drug currently in use that inhibits the activation of several transcription factors (nuclear factor (NF)-AT and NF-κB) critical for T cell activation. We show here that, contrary to the situation in T cells, FK506 activates transcription factor NF-κB in non-lymphoid cells such as fibroblasts and renal mesangial cells. We further show that FK506 induces NF-κB-regulated IL-6 production in vitro and in vivo, in particular in kidney. IL-6 has been shown previously to produce renal abnormalities in vivo, such as mesangioproliferative glomerulonephritis. Similar renal abnormalities were also observed in FK506-treated animals. These results thus suggest a causal relationship between FK506-induced NF-κB activation/IL-6 production and some of FK506-induced renal abnormalities

The J domain of Tpr2 regulates its interaction with the proapoptotic and cell-cycle checkpoint protein, Rad9

金沢大学がん研究所Human Rad9 is a key cell-cycle checkpoint protein that is postulated to function in the early phase of cell-cycle checkpoint control through complex formation with Rad1 and Hus1. Rad9 is also thought to be involved in controlling apoptosis through its interaction with Bcl-2. To explore the biochemical functions of Rad9 in these cellular control mechanisms, we performed two-hybrid screening and identified Tetratricopeptide repeat protein 2 (Tpr2) as a novel Rad9-binding protein. We found that Tpr2 binds not only to Rad9, but also to Radl and Hus1, through its N-terminal tetratricopeptide repeat region, as assessed by in vivo and in vitro binding assays. However, the in vivo and in vitro interactions of Tpr2 with Rad9 were greatly enhanced by the deletion of its C-terminal J domain or by a point mutation in the conserved HPD motif in the J domain, though the binding of Tpr2 to Rad1 and Hus1 was not influenced by these J-domain mutations. We further found: (1) Rad9 transiently dissociates from Tpr2 following heat-shock or UV treatments, but the mutation of the J domain abrogates this transient dissociation of the Tpr2/Rad9 complex; and (2) the J domain of Tpr2 modulates the cellular localization of both Tpr2 itself and Rad9. These results indicate that the J domain of Tpr2 plays a criticai role in the regulation of both physical and functional interactions between Tpr2 and Rad9. © 2001 Academic Press

Structural differences between the closely related RNA helicases, UAP56 and URH49, fashion distinct functional apo-complexes

mRNAを核から細胞質へ輸送するバルクmRNA輸送体の構成因子を解明 がんの早期発見や予後の予測に役立つ可能性のある研究成果. 京都大学プレスリリース. 2024-01-16.mRNA export is an essential pathway for the regulation of gene expression. In humans, closely related RNA helicases, UAP56 and URH49, shape selective mRNA export pathways through the formation of distinct complexes, known as apo-TREX and apo-AREX complexes, and their subsequent remodeling into similar ATP-bound complexes. Therefore, defining the unidentified components of the apo-AREX complex and elucidating the molecular mechanisms underlying the formation of distinct apo-complexes is key to understanding their functional divergence. In this study, we identify additional apo-AREX components physically and functionally associated with URH49. Furthermore, by comparing the structures of UAP56 and URH49 and performing an integrated analysis of their chimeric mutants, we exhibit unique structural features that would contribute to the formation of their respective complexes. This study provides insights into the specific structural and functional diversification of these two helicases that diverged from the common ancestral gene Sub2