Senescence-inducing stress promotes proteolysis of phosphoglycerate mutase via ubiquitin ligase Mdm2.

細胞老化から癌化への変換のカギとなる解糖系制御機構解明に成功 -代謝を標的とした新しい抗がん剤開発に期待-. 京都大学プレスリリース. 2014-02-24.Despite the well-documented clinical significance of the Warburg effect, it remains unclear how the aggressive glycolytic rates of tumor cells might contribute to other hallmarks of cancer, such as bypass of senescence. Here, we report that, during oncogene- or DNA damage-induced senescence, Pak1-mediated phosphorylation of phosphoglycerate mutase (PGAM) predisposes the glycolytic enzyme to ubiquitin-mediated degradation. We identify Mdm2 as a direct binding partner and ubiquitin ligase for PGAM in cultured cells and in vitro. Mutations in PGAM and Mdm2 that abrogate ubiquitination of PGAM restored the proliferative potential of primary cells under stress conditions and promoted neoplastic transformation. We propose that Mdm2, a downstream effector of p53, attenuates the Warburg effect via ubiquitination and degradation of PGAM

Is farmer-to-farmer extension effective? The impact of training on technology adoption and rice farming productivity in Tanzania

Agricultural training is a potentially effective method to diffuse relevant new technologies to increase productivity and alleviate rural poverty in Sub-Saharan Africa (SSA). However, since it is prohibitively expensive to provide direct training to all the farmers in SSA, it is critically important to examine the extent to which technologies taught to a small number of farmers disseminate to non-trained farmers. This paper investigates the technology dissemination pathways among smallholder rice producers within a rural irrigation scheme in Tanzania. As an innovative feature, we compare the performance of three categories of farmers: key farmers, who receive intensive pre-season training at a local training center; intermediate farmers, who are trained by the key farmers; and other ordinary farmers. By collecting and analyzing a unique five-year household-level panel data set, we estimate difference-in-differences models to assess how the gap in performance evolve as the technologies spill over from the trained farmers to the ordinary farmers. To disentangle the technology spillover process, we also examine the extent to which social and geographical network with the key and intermediate farmers influences the adoption of technologies by the ordinary farmers, by incorporating social relationship variables into spatial econometric models. We found that the ordinary farmers who were a relative or residential neighbor of a key or intermediate farmer were more likely to adopt new technologies than those who were not. As a result, while the key farmers’ technology adoption rates rose immediately after the training, those of the non-trained ordinary farmers caught up belatedly. As the technologies disseminated, the paddy yield of the key farmers increased from 3.1 to 5.3 tons per hectare, while the yield of the ordinary farmers increased from 2.6 to 3.7 tons per hectare. Our results suggest the effectiveness and practical potential of farmer-to-farmer extension programs for smallholders in SSA as a cost effective alternative to the conventional farmer training approach

Log N - Log S Relations and Spectral Properties of Sources from the ASCA Large Sky Survey --- their Implications for the Origin of the Cosmic X-ray Background (CXB)

We carried out the first wide-area unbiased survey with the ASCA satellite in the 0.7-10 keV band around a north Galactic-pole region covering a continuous area of 7 square degrees (Large Sky Survey; LSS). To make the best use of ASCA capability, we developed a new source-detection method where the complicated detector responses are fully taken into account. Applying this method to the entire LSS data independently in the total (0.7-7 keV), hard (2-10 keV), and soft (0.7-2 keV) band, we detected 107 sources altogether with sensitivity limits of 6 x 10E-14 (0.7-7 keV), 1 x 10E-13 (2-10 keV), and 2 x 10E-14 erg sE-1 cmE-2 (0.7-2 keV), respectively. A complete list of the detected sources is presented. Based on detailed studies by Monte Carlo simulations, we evaluated effects of the source confusion and accurately derived Log N - Log S relation in each survey band. The Log N - Log S relation in the hard band is located on the extrapolation from the GINGA and HEAO1 results with the Euclidean slope of -3/2, while that in the soft band is consistent with the results by ROSAT. At these flux limits, 30 (+/- 3) percent of the CXB in the 0.7-7 keV band and 23 (+/- 3) percent in the 2-10 keV band have been resolved into discrete sources. The average spectrum of faint sources detected in the total band shows a photon index of 1.63 +/- 0.07 in the 0.7-10 keV range, consistent with the comparison of source counts between the hard and the soft energy band. Those detected in the hard band show a photon index of 1.49 +/- 0.10 in the 2-10 keV range. These spectral properties suggest that contribution of sources with hard energy spectra become significant at a flux of 10E-13 erg sE-1 cmE-2 (2-10 keV). The most plausible candidates are type-II AGNs, as indicated by on-going optical identifications.Comment: 28 pages, 11 figures, to appear in ApJ 518, 1999; figure 1 replaced, minor errors in text correcte

G9a/GLP複合体によりメチル化されたDNAリガーゼ１はUHRF1をDNA複製の場にリクルートしDNAメチル化を制御する

京都大学0048新制・課程博士博士(医科学)甲第21028号医科博第89号新制||医科||6(附属図書館)京都大学大学院医学研究科医科学専攻(主査)教授 斎藤 通紀, 教授 浅野 雅秀, 教授 玉木 敬二学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDFA

The Impact of Training on Technology Adoption and Productivity of Rice Farming in Tanzania: Is Farmer-to-Farmer Extension Effective?

How far can new technologies taught to a small number of selected farmers diffuse to other farmers in a village? In order to answer this question, this paper investigates the impact of JICA training on the adoption of rice cultivation technologies and productivity in an irrigation scheme in Tanzania. By using a unique five-year panel data set and spatial econometric techniques, we found that non-trained farmers learned new technologies from trained farmers through social networks and by observing their plots. As a result, the paddy yield of directly trained farmers increased from 3.1 tons per hectare in 2008 to 4.7 tons per hectare in 2012, while that of non-trained farmers increased from around 2.6 tons per hectare in 2008 to 3.7 tons per hectare in 2012

Non-specific recognition of histone modifications by H3K9bhb antibody.

Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody

Non-specific recognition of histone modifications by H3K9bhb antibody

Summary: Ketone bodies are short-chain fatty acids produced in the liver during periods of limited glucose availability that provide an alternative energy source for the brain, heart, and skeletal muscle. Beyond this metabolic role, β-hydroxybutyrate (BHB), is gaining recognition as a signaling molecule. Lysine β-hydroxybutyrylation (Kbhb) is a newly discovered post-translational modification in which BHB is covalently attached to lysine ε-amino groups. This protein adduct is metabolically sensitive, dependent on BHB concentration, and found on proteins in multiple intracellular compartments. Therefore, Kbhb is hypothesized to be an important component of ketone body-regulated physiology. Kbhb on histones is proposed to be an epigenetic regulator, which links metabolic alterations to gene expression. However, we found that the widely used antibody against β-hydroxybutyrylated lysine 9 on histone H3 (H3K9bhb) also recognizes other modification(s) that likely include acetylation. Therefore, caution must be used when interpreting gene regulation data acquired with the H3K9bhb antibody

Tri-methylation of ATF7IP by G9a/GLP recruits the chromodomain protein MPP8

Abstract Background G9a and the related enzyme GLP were originally identified as histone lysine methyltransferases and then shown to also methylate several other non-histone proteins. Results Here, we performed a comprehensive screen to identify their substrates in mouse embryonic stem cells (mESCs). We identified 59 proteins, including histones and other known substrates. One of the identified substrates, activating transcriptional factor 7-interacting protein 1 (ATF7IP), is tri-methylated at a histone H3 lysine 9 (H3K9)-like mimic by the G9a/GLP complex, although this complex mainly introduces di-methylation on H3K9 and DNA ligase 1 (LIG1) K126 in cells. The catalytic domain of G9a showed a higher affinity for di-methylated lysine on ATF7IP than LIG1, which may create different methylation levels of different substrates in cells. Furthermore, we found that M-phase phosphoprotein 8 (MPP8), known as a H3K9me3-binding protein, recognizes methylated ATF7IP via its chromodomain. MPP8 is also a known component of the human silencing hub complex that mediates silencing of transgenes via SETDB1 recruitment, which is a binding partner of ATF7IP. Although the interaction between ATF7IP and SETDB1 does not depend on ATF7IP methylation, we found that induction of SETDB1/MPP8-mediated reporter-provirus silencing is delayed in mESCs expressing only an un-methylatable mutant of ATF7IP. Conclusions Our findings provide new insights into the roles of lysine methylation in non-histone substrates which are targeted by the G9a/GLP complex and suggest a potential function of ATF7IP methylation in SETDB1/MPP8-mediated transgene silencing