転写制御因子の細胞特異的な協同制御機構を解明する新規計算手法

学位の種別: 課程博士審査委員会委員 : (主査)東京大学教授 油谷 浩幸, 東京大学教授 酒井 寿郎, 東京大学教授 井原 茂男, 東京大学准教授 鯉沼 代造, 東京大学准教授 谷内江 望University of Tokyo(東京大学

Inhibition of cardiac PERK signaling promotes peripartum cardiac dysfunction

Peripartum cardiomyopathy (PPCM) is a life-threatening heart failure occurring in the peripartum period. Although mal-angiogenesis, induced by the 16-kDa N-terminal prolactin fragment (16 K PRL), is involved in the pathogenesis, the effect of full-length prolactin (23 K PRL) is poorly understood. We transfected neonate rat cardiomyocytes with plasmids containing 23 K PRL or 16 K PRL in vitro and found that 23 K PRL, but not 16 K PRL, upregulated protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling, and hypoxia promoted this effect. During the perinatal period, cardiomyocyte-specific PERK homogenous knockout (CM-KO) mice showed PPCM phenotypes after consecutive deliveries. Downregulation of PERK or JAK/STAT signaling and upregulation of apoptosis were observed in CM-KO mouse hearts. Moreover, in bromocriptine-treated CM-KO mice, cardiac function did not improve and cardiomyocyte apoptosis was not suppressed during the peripartum period. These results demonstrate that interaction between 23 K PRL and PERK signaling is cardioprotective during the peripartum term

Downregulation of ERG and FLI1 expression in endothelial cells triggers endothelial-to-mesenchymal transition.

Endothelial cell (EC) plasticity in pathological settings has recently been recognized as a driver of disease progression. Endothelial-to-mesenchymal transition (EndMT), in which ECs acquire mesenchymal properties, has been described for a wide range of pathologies, including cancer. However, the mechanism regulating EndMT in the tumor microenvironment and the contribution of EndMT in tumor progression are not fully understood. Here, we found that combined knockdown of two ETS family transcription factors, ERG and FLI1, induces EndMT coupled with dynamic epigenetic changes in ECs. Genome-wide analyses revealed that ERG and FLI1 are critical transcriptional activators for EC-specific genes, among which microRNA-126 partially contributes to blocking the induction of EndMT. Moreover, we demonstrated that ERG and FLI1 expression is downregulated in ECs within tumors by soluble factors enriched in the tumor microenvironment. These data provide new insight into the mechanism of EndMT, functions of ERG and FLI1 in ECs, and EC behavior in pathological conditions

Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression

Summary: Conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets, along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification. : Kondo et al. find that extracellular acidic pH induces different cellular responses than hypoxia and nutrient starvation. SREBP2 is a key transcriptional regulator of cholesterol biosynthetic genes and ACSS2 in response to extracellular acidification. SREBP2 target genes increase tumor growth in low pH and correlate with decreased survival in patients. Keywords: epigenetics, extracellular low pH, sterol regulatory element-binding protein 2, acyl-CoA synthetase short-chain family member 2, cancer metabolism, tumor microenvironment, nutrient starvation, hypoxia, lacat

A methodology for numerical simulations to a singular limit

Kyushu University 21st Century COE Program Development of Dynamic Mathematics with High Functionality九州大学21世紀COEプログラム「機能数理学の構築と展開」A numerical methodology is proposed for a singular limit of certain reaction-diffusion systems. The limit problem arises in competition-diffusion systems and chemical reaction equations. Convergence of the semi-discrete-in-time solutions obtained by the methodology is proved. In a particular case, a convergence rate is also shown