更新于：2024-11-01

TYMS x HMOX1

更新于：2024-11-01

基本信息

关联

项与 TYMS x HMOX1 相关的药物

SI 1/20

靶点

HMOX1 x TYMS

作用机制

HMOX1抑制剂 [+1]

在研机构

University of Catania

原研机构

University of Catania

在研适应症

前列腺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 TYMS x HMOX1 相关的临床结果

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100 项与 TYMS x HMOX1 相关的转化医学

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0 项与 TYMS x HMOX1 相关的专利（医药）

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项与 TYMS x HMOX1 相关的文献（医药）

2009-08-01·Journal of Biological Chemistry2区 · 生物学

Oligomerization Is Crucial for the Stability and Function of Heme Oxygenase-1 in the Endoplasmic Reticulum

2区 · 生物学

Article

作者: Ming-Jing Hwang ; Chinpan Chen ; Lee-Young Chau ; Hsuan-Wen Hwang ; Kuan-Yu Chou ; Jay-Ron Lee ; Ching-Shu Suen ; Ru-Chi Shieh

Heme oxygenase-1 (HO-1), a stress-inducible enzyme anchored in the endoplasmic reticulum (ER) by a single transmembrane segment (TMS) located at the C terminus, interacts with NADPH cytochrome P450 reductase and biliverdin reductase to catalyze heme degradation to biliverdin and its metabolite, bilirubin. Previous studies suggested that HO-1 functions as a monomer. Using chemical cross-linking, co-immunoprecipitation, and fluorescence resonance energy transfer (FRET) experiments, here we showed that HO-1 forms dimers/oligomers in the ER. However, oligomerization was not observed with a truncated HO-1 lacking the C-terminal TMS (amino acids 266-285), which exhibited cytosolic and nuclear localization, indicating that the TMS is essential for the self-assembly of HO-1 in the ER. To identify the interface involved in the TMS-TMS interaction, residue Trp-270, predicted by molecular modeling as a potential interfacial residue of TMS alpha-helices, was mutated, and the effects on protein subcellular localization and activity assessed. The results showed that the W270A mutant was present exclusively in the ER and formed oligomers with similar activity to those of the wild type HO-1. Interestingly, the W270N mutant was localized not only in the ER, but also in the cytosol and nucleus, suggesting it is susceptible to proteolytic cleavage. Moreover, the microsomal HO activity of the W270N mutant was significantly lower than that of the wild type. The W270N mutation appears to interfere with the oligomeric state, as revealed by a lower FRET efficiency. Collectively, these data suggest that oligomerization, driven by TMS-TMS interactions, is crucial for the stabilization and function of HO-1 in the ER.

1988-11-01·Molecular and Cellular Biology3区 · 生物学

Transcriptional Regulation of the Cell Cycle-Dependent Thymidylate Synthase Gene of Saccharomyces cerevisiae

3区 · 生物学

Article

作者: McIntosh, Evan M. ; Storms, Reginald K. ; Ord, Robin W.

We have previously shown that transcript levels expressed from the yeast TMP1 gene fluctuate periodically during the yeast cell cycle. However, it was not known whether periodic expression resulted from a regulatory mechanism acting at the level of transcription or a regulatory mechanism acting at the level of cell cycle stage-dependent changes in the stability of the TMP1 transcript. In this report we now show that the periodic expression of TMP1 transcript is primarily controlled at the level of its transcription by sequences which are upstream of its transcription initiation sites. We also localized the upstream sequences necessary for periodic transcription to a 150-base-pair region and show that this region encodes an element(s) with the properties of a periodic upstream activating sequence. The regulatory region defined in this study apparently does not contain consensus sequences similar to those reported for the cell cycle-regulated HO endonuclease or for the histone H2A and H2B genes of Saccharomyces cerevisiae.

BMC Neurology

Leukocyte differential gene expression prognostic value for high versus low seizure frequency in temporal lobe epilepsy

Article

作者: Sprissler, Ryan ; Alan, Albert ; Weinand, Martin ; Hammer, Michael ; Labiner, David ; Joshi, Neil

AbstractBackgroundThis study was performed to test the hypothesis that systemic leukocyte gene expression has prognostic value differentiating low from high seizure frequency refractory temporal lobe epilepsy (TLE).MethodsA consecutive series of patients with refractory temporal lobe epilepsy was studied. Based on a median baseline seizure frequency of 2.0 seizures per month, low versus high seizure frequency was defined as ≤ 2 seizures/month and > 2 seizures/month, respectively. Systemic leukocyte gene expression was analyzed for prognostic value for TLE seizure frequency. All differentially expressed genes were analyzed, with Ingenuity® Pathway Analysis (IPA®) and Reactome, to identify leukocyte gene expression and biological pathways with prognostic value for seizure frequency.ResultsThere were ten males and six females with a mean age of 39.4 years (range: 16 to 62 years, standard error of mean: 3.6 years). There were five patients in the high and eleven patients in the low seizure frequency cohorts, respectively. Based on a threshold of twofold change (p < 0.001, FC > 2.0, FDR < 0.05) and expression within at least two pathways from both Reactome and Ingenuity® Pathway Analysis (IPA®), 13 differentially expressed leukocyte genes were identified which were all over-expressed in the low when compared to the high seizure frequency groups, including NCF2, HMOX1, RHOB, FCGR2A, PRKCD, RAC2, TLR1, CHP1, TNFRSF1A, IFNGR1, LYN, MYD88, and CASP1. Similar analysis identified four differentially expressed genes which were all over-expressed in the high when compared to the low seizure frequency groups, including AK1, F2R, GNB5, and TYMS.ConclusionsLow and high seizure frequency TLE are predicted by the respective upregulation and downregulation of specific leukocyte genes involved in canonical pathways of neuroinflammation, oxidative stress and lipid peroxidation, GABA (γ-aminobutyric acid) inhibition, and AMPA and NMDA receptor signaling. Furthermore, high seizure frequency-TLE is distinguished prognostically from low seizure frequency-TLE by differentially increased specific leukocyte gene expression involved in GABA inhibition and NMDA receptor signaling. High and low seizure frequency patients appear to represent two mechanistically different forms of temporal lobe epilepsy based on leukocyte gene expression.