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| 1.
論文 |
論文
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Shamma, Awad ; Suzuki, Misa ; Hayashi, Naoyuki ; Kobayashi, Masahiko ; Sasaki, Nobunari ; Nishiuchi, Takumi ; Doki, Yuichiro ; Okamoto, Takahiro ; Kohno, Susumu ; Muranaka, Hayato ; Kitajima, Shunsuke ; Yamamoto, Ken-ichi ; Takahashi, Chiaki
概要:
The retinoblastoma tumor suppressor gene (RB) product has been implicated in epigenetic control of gene expression owing to its ability to physically bind to many chromatin modifiers. However, the biological and clinical significance of
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this activity was not well elucidated. To address this, we performed genetic and epigenetic analyses in an Rb-deficient mouse thyroid C cell tumor model. Here we report that the genetic interaction of Rb and ATM regulates DNMT1 protein stability and hence controls the DNA methylation status in the promoters of at least the Ink4a, Shc2, FoxO6, and Noggin genes. Furthermore, we demonstrate that inactivation of pRB promotes Tip60 (acetyltransferase)-dependent ATM activation; allows activated ATM to physically bind to DNMT1, forming a complex with Tip60 and UHRF1 (E3 ligase); and consequently accelerates DNMT1 ubiquitination driven by Tip60-dependent acetylation. Our results indicate that inactivation of the pRB pathway in coordination with aberration in the DNA damage response deregulates DNMT1 stability, leading to an abnormal DNA methylation pattern and malignant progression.
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| 2.
論文 |
論文
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Salah, Mohammed ; Nishimoto, Yuuki ; Kohno, Susumu ; Kondoh, Atsushi ; Kitajima, Shunsuke ; Muranaka, Hayato ; Nishiuchi, Takumi ; Ibrahim, Ahmed ; Yoshida, Akiyo ; Takahashi, Chiaki
概要:
Mutations in RB and PTEN are linked to castration resistance and poor prognosis in prostate cancer. Identification of ge
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nes that are regulated by these tumor suppressors in a context that recapitulates cancer progression may be beneficial for discovering novel therapeutic targets. Although various genetically engineered mice thus far provided tumor models with various pathological stages, they are not ideal for detecting dynamic changes in gene transcription. Additionally, it is difficult to achieve an effect specific to tumor progression via gain of functions of these genes. In this study, we developed an in vitro model to help identify RB- and PTEN-loss signatures during the malignant progression of prostate cancers. Trp53−/−; Rbf/f, Trp53−/−; Ptenf/f, and Trp53−/−; Rbf/f; Ptenf/f prostate epithelial cells were infected with AD-LacZ or AD-Cre. We found that deletion of Rb, Pten or both stimulated prostasphere formation and tumor development in immune-compromised mice. The GO analysis of genes affected by the deletion of Rb or Pten in Trp53−/− prostate epithelial cells identified a number of genes encoding cytokines, chemokines and extracellular matrix remodeling factors, but only few genes related to cell cycle progression. Two genes (Il-6 and Lox) were further analyzed. Blockade of Il-6 signaling and depletion of Lox significantly attenuated prostasphere formation in 3D culture, and in the case of IL-6, strongly suppressed tumor growth in vivo. These findings suggest that our in vitro model may be instrumental in identifying novel therapeutic targets of prostate cancer progression, and further underscore IL-6 and LOX as promising therapeutic targets. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.<br />Embargo Period 12 months
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| 3.
論文 |
論文
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Yoshida, Akiyo ; Kitajima, Shunsuke ; Li, Fengkai ; Cheng, Chaoyang ; Takegami, Yujiro ; Kohno, Susumu ; Wan, Yuan Song ; Hayashi, Naoyuki ; Muranaka, Hayato ; Nishimoto, Yuuki ; Nagatani, Naoko ; Nishiuchi, Takumi ; Thai, Tran C ; Suzuki, Sawako ; Nakao, Shinji ; Tanaka, Tomoaki ; Hirose, Osamu ; Barbie, David A. ; Takahashi, Chiaki
概要:
We established an in vitro cell culture system to determine novel activities of the retinoblastoma (Rb) protein during tumor progression. Rb depletion in p53-null mouse-derived soft tissue sarcoma cells induced a spherogenic
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phenotype. Cells retrieved from Rb-depleted spheres exhibited slower proliferation and less efficient BrdU incorporation, however, much higher spherogenic activity and aggressive behavior. We discovered six miRNAs, including mmu-miR-18a, -25, -29b, -140, -337, and -1839, whose expression levels correlated tightly with the Rb status and spherogenic activity. Among these, mmu-miR-140 appeared to be positively controlled by Rb and to antagonize the effect of Rb depletion on spherogenesis and tumorigenesis. Furthermore, among genes potentially targeted by mmu-miR-140, Il-6 was upregulated by Rb depletion and downregulated by mmu-mir-140 overexpression. Altogether, we demonstrate the possibility that mmu-mir-140 mediates the Rb function to downregulate Il-6 by targeting its 3'-untranslated region. Finally, we detected the same relationship among RB, hsa-miR-140 and IL-6 in a human breast cancer cell line MCF-7. Because IL-6 is a critical modulator of malignant features of cancer cells and the RB pathway is impaired in the majority of cancers, hsa-miR-140 might be a promising therapeutic tool that disrupts linkage between tumor suppressor inactivation and pro-inflammatory cytokine response.<br />Supplementary Table1 and Supplementary Table2: We offer the table data with an Excel file
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