Jmjd5, a JmjC domain containning protein, modulates embroyonic cell proliferation through the regulation of p53-target genes expression

The 3rd International Symposium on Carcinogenic Spiral & International Symposium on Tumor Biology in Kanazawa, [DATE]: January 24(Thu)-25(Fri),2013, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Infection/Inflammation-Assisted Acceleration of the Carcinogenic Spiral and its Alteration through Vector Conversion of the Host Response to Tumors / Scientific Research on Innovative Areas, a MEXT Grant-in Aid Projec

Steroidogenic enzymes in the CP

Peripherally derived steroids affect steroid production in the brain via the blood–brain barrier. However, steroid concentrations are lower in the cerebrospinal fluid than those in the blood, indicating restricted influx of steroids because of their metabolization by choroid plexus (CP) epithelial cells. Here, we analyzed the gene expression of steroidogenic enzymes [cholesterol side-chain cleavage enzyme (P450scc), 17α-hydroxylase/C17-C20 lyase (P450c17), 3β-hydroxysteroid dehydrogenase (3β -HSD), 17β-hydroxysteroid dehydrogenase type 1 (17β -HSD1), aromatase (Cyp19a1), and 5α-reductase type 1 (5α -R1)]. These genes were expressed to a lesser extent in the CP than in the testis and to a similar extent in the cerebral cortex. However, P450scc levels were higher in the CP than in the cerebral cortex, whereas Cyp19a1 levels showed the opposite trend. We also evaluated the effects of orchiectomy and testosterone on the expression of these genes. P450c17 and 5α -R1 levels were unaffected by orchiectomy, whereas P450scc and 3β -HSD levels were increased and decreased, respectively. Cyp19a1 expression increased upon testosterone treatment, whereas that of 17β -HSD decreased upon orchiectomy or administration of testosterone. Immunohistochemistry analysis revealed that 17β -HSD was expressed in the cytoplasm of CP epithelial cells. These results indicate that CP epithelial cells synthesize and convert the certain types of steroids to contribute to the homeostasis of steroids in the brain

Roles of histone methyl-modifying enzymes in development and progression of cancer

がん進展制御研究所Retroviral insertional mutagenesis in mice is considered a powerful forward genetic strategy to identify disease genes involved in cancer. Our high-throughput screens led to frequent identification of the genes encoding the enzymes engaged in histone lysine methylation. Histone methylation can positively or negatively impact on gene transcription, and then fulfill important roles in developmental control and cell-fate decisions. A tremendous amount of progress has accelerated the characterization of histone methylations and the enzymes that regulate them. Deregulation of these histone methyl-modifying enzymes has been increasingly recognized as a hallmark of cancer in the last few years. However, in most cases, we have only limited understanding for the molecular mechanisms by which these enzymes contribute to cancer development and progression. In this review, we summarize the current knowledge regarding some of the best-validated examples of histone lysine methyltransferases and demethylases associated with oncogenesis and discuss their potential mechanisms of action. © 2013 Japanese Cancer Association

Jmjd5, an H3K36me2 histone demethylase, modulates embryonic cell proliferation through the regulation of Cdkn1a expression.

Covalent modifications of histones play an important role in chromatin architecture and dynamics. In particular, histone lysine methylation is important for transcriptional control during diverse biological processes. The nuclear protein Jmjd5 (also called Kdm8) is a histone lysine demethylase that contains a JmjC domain in the C-terminal region. In this study, we have generated Jmjd5-deficient mice (Jmjd5Δ/Δ) to investigate the in vivo function of Jmjd5. Jmjd5Δ/Δ embryos showed severe growth retardation, resulting in embryonic lethality at the mid-gestation stage. Mouse embryonic fibroblasts (MEFs) derived from Jmjd5 hypomorphic embryos (Jmjd5neo/neo) also showed the growth defect. Quantitative PCR analysis of various cell cycle regulators indicated that only Cdkn1a expression was upregulated in Jmjd5neo/neo MEFs and Jmjd5Δ/Δ embryos. A knockdown assay with Cdkn1a-specific small interfering RNAs revealed that the growth defect of Jmjd5neo/neo MEFs was significantly rescued. In addition, a genetic study using Jmjd5Δ/Δ; Cdkn1aΔ/Δ double-knockout mice showed that the growth retardation of Jmjd5Δ/Δ embryos was partially rescued by Cdkn1a deficiency. Chromatin immunoprecipitation analysis showed that increased di-methylated lysine 36 of histone H3 (H3K36me2) and reduced recruitment of endogenous Jmjd5 were detected in the transcribed regions of Cdkn1a in Jmjd5neo/neo MEFs. Taken together, these results suggest that Jmjd5 physiologically moderates embryonic cell proliferation through the epigenetic control of Cdkn1a expression.Accepted December 16, 2011

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC

Poster Session

International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discoverry in Academics 2014 [DATE]: January 23(Thu)-24(Fri),2014, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Kanazawa Association of Tumor Biologists / Cancer Research Institute, Kanazawa Universit

がん関連遺伝子Jmjd5の新しい遺伝子発現制御機構の解明

金沢大学がん進展制御研究所Jumonji C (JmjC）ファミリーに属するJmjd5は、ウイルス感染発がんモデルマウスを用いたスクリーニングによってがん関連遺伝子候補として同定された。これまで私たちは、Jmjd5欠損マウスを用いて細胞増殖抑制因子Cdkn1aの発現を制御することを報告した。本研究では、より詳細な実験の結果、主要ながん抑制遺伝子p53と直接結合することでp53蛋白質の標的遺伝子座へのリクルートを負に制御することを発見した。マウス胚発生においてp53の発現は翻訳レベルで厳密に抑えられていることが知られている。Jmjd5は発生期のp53シグナル抑制機構の一端を担う、新しい遺伝子である可能性が強く示唆された。We previously identified Jmjd5 as a candidate cancer-related gene by retroviral mutagenesis. Jmjd5 belongs to Jumonji C (JmjC) family, some of which encode histone demethylase. Our genetic studies using Jmjd5 deficient mice showed that Jmjd5 was a regulator for Cdkn1a expression during mouse embryogenesis. In this study, we found that a subset of p53-regulated genes highly expressed in Jmjd5 knockout embryos. We also showed that Jmjd5 protein could directly associate with p53 protein, one of the most famous tumor suppressor genes, and inhibited the recruitment of endogenous p53 protein at several p53 target loci such as Cdkn1a. Pmaip1 and Mdm2. In general, aberrant activation of p53 signaling leads to embryonic lethality, suggesting that maintaining a fine balance of p53 translational level is important for normal development. Thus, Jmjd5 may keep basal level of p53 signaling in embryonic cells through the control of p53 recruitment at its target genes.研究課題/領域番号:25460266, 研究期間(年度):2013-04-01 – 2016-03-3

A New Dawn for the Use of Artificial Intelligence in Gastroenterology, Hepatology and Pancreatology

Artificial intelligence (AI) is rapidly becoming an essential tool in the medical field as well as in daily life. Recent developments in deep learning, a subfield of AI, have brought remarkable advances in image recognition, which facilitates improvement in the early detection of cancer by endoscopy, ultrasonography, and computed tomography. In addition, AI-assisted big data analysis represents a great step forward for precision medicine. This review provides an overview of AI technology, particularly for gastroenterology, hepatology, and pancreatology, to help clinicians utilize AI in the near future

ウイルス挿入変異法で同定された新規がん関連遺伝子Jmjd5の機能解析

金沢大学がん進展制御研究所ウイルス感染モデルマウスを用いたスクリーニングによって、JmjCファミリーに属する遺伝子の約半数が癌の原因遺伝子候補として発見された。そのうちの1つJmjd5に関して、遺伝子改変マウス(Jmjd5^囗^)の表現型解析を行った結果、Jmjd5はp21遺伝子発現のエピジェネティックな制御因子の1つとして胚細胞の増殖に必須な遺伝子である事を2012年、Development誌で報告した。Our retroviral insertional mutagenesis in mice showed frequent identification of JmjC family genes as novel candidates cancer-related genes. Jmjd5, one of the family genes, was also a target for the retrovirus, and we generated Jmjd5-deficientmice (Jmjd5△囗△) to investigate the physiological role of Jmjd5. We showed that Jmjd5 was involved in embryonic cell proliferation by fine-tuning the expression of p21 (Ishimura et al., Development 2012).研究課題/領域番号:23790220, 研究期間(年度):2011-201