Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains

Asymmetric cell division of Drosophila neural stem cells or neuroblasts is an important process which gives rise to two different daughter cells, one of which is the stem cell itself and the other, a committed or differentiated daughter cell. During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. We identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. It preferentially binds to the aPKC/Bazooka/Partition Defective 6 complex and stabilizes aPKC levels. In clu mutants, Miranda (Mira) and Numb are mislocalized in small percentages of dividing neuroblasts. Adult mutants are short-lived with severe locomotion defects. Clu promotes tumorigenesis caused by loss of function of lethal(2) giant larvae (lgl) in the larval brain. Removal of clu in lgl mutants rescues Mira and Numb mislocalization and restores the enlarged brain size. Western blot analyses indicate that the rescue is due to the down-regulation of aPKC levels in the lgl clu double mutant. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. Our study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.     

Purification and Some Properties of Dipeptidyl Carboxypeptidase from Bacillus pumilus

An intracellular protease from a bacterium, Bacillus pumilus HL721, was purified about 5000-fold by Chromatography with a Q-Sepharose Fast Flow column, TSK-gel HA-1000 glass column, and TSK-gel G3000SWXL column using Bz-Gly-Ala-Pro as a substrate. The enzyme was the most active at pH around 7.5 and stable from 4.5 and 8.0. The enzyme activity was inhibited by Cu²⁺, EDTA, N-ethylmaleimide, o-phenanthroline, and p-chloromercuribenzoic acid. The molecular weight of the enzyme was 155,000 by gel filtration. The enzyme removed dipeptide from the carboxyl end of some peptides used as substrates. From these results the enzyme seems to be a dipeptidyl carboxypeptidase.     

ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages

Differentiation to different types of macrophages determines their distinct functions. Tumor-associated macrophages (TAMs) promote tumorigenesis owing to their proangiogenic and immune-suppressive functions similar to those of alternatively activated (M2) macrophages. We report that reactive oxygen species (ROS) production is critical for macrophage differentiation and that inhibition of superoxide (O²⁻) production specifically blocks the differentiation of M2 macrophages. We found that when monocytes are triggered to differentiate, O²⁻ is generated and is needed for the biphasic ERK activation, which is critical for macrophage differentiation. We demonstrated that ROS elimination by butylated hydroxyanisole (BHA) and other ROS inhibitors blocks macrophage differentiation. However, the inhibitory effect of ROS elimination on macrophage differentiation is overcome when cells are polarized to classically activated (M1), but not M2, macrophages. More importantly, the continuous administration of the ROS inhibitor BHA efficiently blocked the occurrence of TAMs and markedly suppressed tumorigenesis in mouse cancer models. Targeting TAMs by blocking ROS can be a potentially effective method for cancer treatment.     

微小RNA-129在肿瘤发生中的作用机制

微小RNA-129（microRNA-129, miR-129）是一种能产生miR-129-5p、miR-129-1-3p和miR-129-2-3p等3种成熟产物的miRNA,它们在细胞生长、发育、癌变等生命过程中有重要作用. miR-129在多种常见肿瘤中呈现高表达（如：胃癌和肺癌）或低表达（如：乳腺癌和食管鳞状细胞癌）的多样现象,而且这种异常表达与肿瘤的发生发展有密切联系. miR-129通过作用于性别决定区Y框蛋白4（sex-determining-region Y-box 4, SOX4）、细胞周期蛋白依赖激酶6（cyclin-dependent kinase 6, Cdk6）、含缬酪肽蛋白（valosin containing protein, VCP）和磷脂酰肌醇蛋白聚糖-3（glypican-3, GP3）等多种靶基因而在肿瘤发生、发展过程中起着重要作用.     

HER-2/neu x aromatase double transgenic mice model: the effects of aromatase overexpression on mammary tumorigenesis

A majority of breast cancers are hormone-responsive, and require estrogen for growth, and respond to hormonal therapy that blocks estrogen receptor action. Breast tumors with low levels of or completely lacking estrogen receptor fail to respond to antiestrogen therapy yet require estrogen for tumor initiation. To address the importance of local estrogen in oncogene-mediated breast tumorigenesis, we have crossed MMTV-aromatase with MMTV-HER2/neu and examined the incidence of breast cancer in double transgenic mice in comparison with parental strains. Double transgenic mice show normal mammary development and express both transgenes at similar levels to that of parental strains. Tumor incidence in double transgenic mice (<5%) decreased compared to HER2/neu mice (>65%). In addition to a significant decrease in tumorigenesis, these mice expressed ER as well as high levels of ERβ along with decreased levels of cyclin D1 and phosphorylated pRb among other changes. Furthermore, experiments using THC (ER-agonist and ERβ-antagonist) clearly demonstrate the critical role of ERβ in HER2/neu-mediated tumorigenesis. These studies provide the first genetic evidence that estrogen receptor, mainly ERβ than ER and its dependent changes play an important role in regulating mammary tumorigenesis. These findings provide further evidence for development and testing of novel therapeutic approaches based on selective regulation of estrogen receptors (ER and β)-dependent actions for the treatment and prevention of breast cancers.     

UCP2 Overexpression Redirects Glucose into Anabolic Metabolic Pathways

Uncoupling protein 2 (UCP2) is often upregulated in cancer cells. The UCP2 upregulation is positively correlated with enhanced proliferation, tumorigenesis, and metabolic alterations, thus suggesting that UCP2 upregulation can play a key role in sensing metabolic changes to promote tumorigenesis. To determine the global metabolic impact of UCP2 upregulation, ¹³C₆ glucose as a source molecule is used to “trace” the metabolic fate of carbon atoms derived from glucose. UCP2 overexpression in skin epidermal cells enhances the incorporation of ¹³C label to pyruvate, tricarboxylic acid cycle intermediates, nucleotides, and amino acids, suggesting that UCP2 upregulation reprograms cellular metabolism toward macromolecule synthesis. To the best of our knowledge, this is the first study to bring to light the overall metabolic differences caused by UCP2 upregulation.     

Single-Cell Transcriptomics Uncovers Glial Progenitor Diversity and Cell Fate Determinants during Development and Gliomagenesis

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