Publications by authors named "Joydeep Mukherjee"

94 Publications

Stroke-like episodes with cerebellar ataxia as presenting manifestation of adult-onset anti-N-methyl D-aspartate receptor encephalitis: an unusual presentation.

Acta Neurol Belg 2021 Aug 3;121(4):1093-1095. Epub 2021 Jul 3.

Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, 560029, India.

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http://dx.doi.org/10.1007/s13760-021-01735-wDOI Listing
August 2021

Role of intertidal microbial communities in carbon dioxide sequestration and pollutant removal: A review.

Mar Pollut Bull 2021 Sep 18;170:112626. Epub 2021 Jun 18.

School of Environmental Studies, Jadavpur University, 700032, India. Electronic address:

Intertidal microbial communities occur as biofilms or microphytobenthos (MPB) which are sediment-attached assemblages of bacteria, protozoa, fungi, algae, diatoms embedded in extracellular polymeric substances. Despite their global occurrence, they have not been reviewed in light of their structural and functional characteristics. This paper reviews the importance of such microbial communities and their importance in carbon dioxide sequestration as well as pollutant bioremediation. Global annual benthic microalgal productivity was 500 million tons of carbon, 50% of which contributed towards the autochthonous carbon fixation in the estuaries. Primary production by MPB was 27-234 gCmy in the estuaries of Asia, Europe and the United States. Mechanisms of heavy metal removal remain to be tested in intertidal communities. Cyanobacteria facilitate hydrocarbon degradation in intertidal biofilms and microbial mats by supporting the associated sulfate-reducing bacteria and aerobic heterotrophs. Physiological cooperation between the microorganisms in intertidal communities imparts enhanced ability to utilize polycyclic aromatic hydrocarbon pollutants by these microorganisms than mono-species communities. Future research may be focused on biochemical characteristics of intertidal mats and biofilms, pollutant-microbial interactions and ecosystem influences.
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http://dx.doi.org/10.1016/j.marpolbul.2021.112626DOI Listing
September 2021

Assessing the effect of herbicide diuron on river biofilm: A statistical model.

Chemosphere 2021 Nov 4;282:131104. Epub 2021 Jun 4.

School of Environmental Studies. Jadavpur University. Kolkata, 700032, India. Electronic address:

River biofilm communities are the first ones to be exposed to all toxic discharges received via run off from agricultural fields. Hence, changes in river biofilm community structure and growth pattern are considered as indicator of overall health of lotic ecosystem. Toxicants have effect on biofilm biomass, photosynthetic efficiency and chlorophyll a concentrations. Mathematical models may be applied to estimate the overall vigor of riverine ecosystems considering biofilms as indicators. Herein, previous empirical data of Ricart et al. (2009) on long term effects of environmentally relevant concentrations of diuron on biofilm communities of the River Llobregat, Spain was considered as our model inputs. Our objective is to understand the influence of diuron, chlorophyll a concentrations and photosynthetic efficiency on biovolume using a statistical model. The non-linear relationships between biovolume (dependent variable) and diuron, chlorophyll a concentrations and photosynthetic efficiency (independent variables) were represented by constructing three separate basis functions based on day 8 empirical data. Biovolume, due to nonlinear influence as yielded by the basis functions were used in a multiple linear regression model to estimate the net biovolume. Model validation was done based on day 29 empirical data. The experimentally determined biovolume and our model estimated biovolume showed similar trends. Also, diuron and photosynthetic efficiency had significant (p < 0.05) influence on biovolume. Since, the predominance of diatoms as biofilms within periphytic layers is very common in lotic systems, estimation of changes in diatom biovolume will be significant to assess the effect of herbicides. Diatom biovolume of any day (for example day 22) mentioned in the experimental study may be determined by this model, without the requirement of tedious manual biovolume calculation. Our model will be useful in numerous other studies undertaken on the toxic effect of pollutants on biofilms to quickly and accurately estimate the biofilm biovolume.
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http://dx.doi.org/10.1016/j.chemosphere.2021.131104DOI Listing
November 2021

Interactive effect of elevated tropospheric ozone and carbon dioxide on radiation utilisation, growth and yield of chickpea (Cicer arietinum L.).

Int J Biometeorol 2021 Nov 28;65(11):1939-1952. Epub 2021 May 28.

Centre for Environmental Science and Climate Resilient Agriculture, ICAR-IARI, New Delhi, 110012, India.

An experiment was conducted in the Free Air Ozone and Carbon dioxide Enrichment (FAOCE) facility to study the impact of elevated O, CO and their interaction on chickpea crop (cv. Pusa-5023) in terms of phenology, biophysical parameters, yield components, radiation interception and use efficiency. The crop was exposed to elevated O (EO:60ppb), CO (EC:550 ppm) and their combined interactive treatment (ECO: EC+EO) during the entire growing season. Results revealed that the crop's total growth period was shortened by 10, 14 and 17 days under elevated CO, elevated O and the combined treatment, respectively. Compared to ambient condition, the leaf area index (LAI) under elevated CO was higher by 4 to 28%, whilst it is reduced by 7.3 to 23.8% under elevated O. The yield based radiation use efficiency (RUE) was highest under elevated CO (0.48 g MJ), followed by combined (0.41 g MJ), ambient (0.38 g MJ) and elevated O (0.32 g MJ) treatments. Elevated O decreased RUE by 15.78% over ambient, and the interaction results in a 7.8% higher RUE. The yield was 31.7% more under elevated CO and 21.9% lower in elevated O treatment as compared to the ambient. The combined interactive treatment recorded a higher yield as compared to ambient by 9.7%. Harvest index (HI) was lowest under elevated O (36.10%), followed by ambient (39.18%), combined (40.81%), and highest was under elevated CO (44.18%). Chickpea showed a positive response to elevated CO resulting a 5% increase in HI as compared to ambient condition. Our findings quantified the positive and negative impacts of elevated O, CO and their interaction on chickpea and revealed that the negative impacts of elevated O can be compensated by elevated CO in chickpea. This work promotes the understanding of crop behaviour under elevated O, CO and their interaction, which can be used as valuable inputs for radiation-based crop simulation models to simulate climate change impact on chickpea crop.
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http://dx.doi.org/10.1007/s00484-021-02150-9DOI Listing
November 2021

A subset of PARP inhibitors induces lethal telomere fusion in ALT-dependent tumor cells.

Sci Transl Med 2021 05;13(592)

Department of Neurosurgery and The Brain Tumor Center, University of California-San Francisco, San Francisco, CA 94158, USA.

About 10% of all tumors, including most lower-grade astrocytoma, rely on the alternative lengthening of telomere (ALT) mechanism to resolve telomeric shortening and avoid limitations on their growth. Here, we found that dependence on the ALT mechanism made cells hypersensitive to a subset of poly(ADP-ribose) polymerase inhibitors (PARPi). We found that this hypersensitivity was not associated with PARPi-created genomic DNA damage as in most PARPi-sensitive populations but rather with PARPi-induced telomere fusion. Mechanistically, we determined that PARP1 was recruited to the telomeres of ALT-dependent cells as part of a DNA damage response. By recruiting MRE11 and BRCC3 to stabilize TRF2 at the ends of telomeres, PARP1 blocked chromosomal fusion. Exposure of ALT-dependent tumor cells to a subset of PARPi induced a conformational change in PARP1 that limited binding to MRE11 and BRCC3 and delayed release of the TRF2-mediated block on lethal telomeric fusion. These results therefore provide a basis for PARPi treatment of ALT-dependent tumors, as well as establish chromosome fusion as a biomarker of their activity.
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http://dx.doi.org/10.1126/scitranslmed.abc7211DOI Listing
May 2021

Phosphoglycerate mutase 1 (PGAM1) overexpression promotes radio- and chemoresistance in gliomas by activating the DNA damage response.

Mol Cell Oncol 2021 22;8(2):1875804. Epub 2021 Mar 22.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA, USA.

The glycolytic enzyme PGAM1 is overexpressed in gliomas where it efficiently facilitates the repair of DNA damage. Mechanistically, PGAM1 prevents inactivation of the ataxia-telangiectasia mutated (ATM) signaling pathway by sequestering the wild-type p53-induced phosphatase 1 (WIP1) in the cytoplasm. Genetic inhibition of PGAM1 expression subsequently sensitizes glioma cells against irradiation and chemotherapy-induced DNA damage.
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http://dx.doi.org/10.1080/23723556.2021.1875804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018509PMC
March 2021

Non-invasive assessment of telomere maintenance mechanisms in brain tumors.

Nat Commun 2021 01 4;12(1):92. Epub 2021 Jan 4.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

Telomere maintenance is a universal hallmark of cancer. Most tumors including low-grade oligodendrogliomas use telomerase reverse transcriptase (TERT) expression for telomere maintenance while astrocytomas use the alternative lengthening of telomeres (ALT) pathway. Although TERT and ALT are hallmarks of tumor proliferation and attractive therapeutic targets, translational methods of imaging TERT and ALT are lacking. Here we show that TERT and ALT are associated with unique H-magnetic resonance spectroscopy (MRS)-detectable metabolic signatures in genetically-engineered and patient-derived glioma models and patient biopsies. Importantly, we have leveraged this information to mechanistically validate hyperpolarized [1-C]-alanine flux to pyruvate as an imaging biomarker of ALT status and hyperpolarized [1-C]-alanine flux to lactate as an imaging biomarker of TERT status in low-grade gliomas. Collectively, we have identified metabolic biomarkers of TERT and ALT status that provide a way of integrating critical oncogenic information into non-invasive imaging modalities that can improve tumor diagnosis and treatment response monitoring.
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http://dx.doi.org/10.1038/s41467-020-20312-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782549PMC
January 2021

Whole-Genome Sequence of Cyanobacterium sp. AP17, Isolated from an Indian Mangrove Forest.

Microbiol Resour Announc 2020 Oct 29;9(44). Epub 2020 Oct 29.

School of Environmental Studies, Jadavpur University, Kolkata, India

sp. AP17 is the second distinct species of the genus, and it differs from the first () in 16S-23S internal transcribed spacer (ITS) sequence, morphology, and optimal salinity. The genome size is 6.37 Mbp; 4,801 protein-coding genes, 74 tRNAs, and 5 each of the 16S, 23S, and 5S rRNAs constitute the genome.
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http://dx.doi.org/10.1128/MRA.00808-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595944PMC
October 2020

Bacillus rugosus sp. nov. producer of a diketopiperazine antimicrobial, isolated from marine sponge Spongia officinalis L.

Antonie Van Leeuwenhoek 2020 Nov 16;113(11):1675-1687. Epub 2020 Sep 16.

School of Environmental Studies, Jadavpur University, Kolkata, 700 032, India.

A novel Gram-positive and endospore-forming bacterium assigned as strain SPB7 which is also a new source of a cyclic diketopiperazine (3S,6S)-3,6-diisobutylpiperazine-2,5-dione is described. A polyphasic (biochemical, phenotypic and genotypic) approach was used to clarify the taxonomic affiliation of this strain. The partial and complete 16S rRNA gene sequences revealed that strain SPB7 is a member of the Bacillus genus [showing high similarity (> 98.70%) with Bacillus spizizenii NRRL B-23049, Bacillus tequilensis KCTC 13622, Bacillus inaquosorum KCTC 13429 and Bacillus cabrialesii TE3]. The maximum values for average nucleotide identity (ANI) and in silico DNA-DNA hybridization (GGDC, Formula 2) of strain SPB7 was obtained for twenty-five strains of Bacillus spizizenii (ANI 95.01-95.48% and GGDC 62.70-60.00%). The whole-genome phylogenetic relationship showed that SPB7 formed an individual and separated clade with the Bacillus spizizenii group. Principal cellular fatty acids identified in strain SPB7 were anteiso C, anteiso C, iso C, iso C, C, C 3OH and iso C . Polar lipid profile showed presence of diphosphotidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, two unknown phospholipids and five unknown lipids. Cells were rod shaped, catalase, oxidase-positive and motile. Growth occurred at 20-45 °C (optimal 35 °C), at pH 6.0-10.0 (optimal pH 8) and 0-10% (w/v) NaCl (optimal 2%). The phenotypic, biochemical, and genotypic traits of strain SPB7 strongly supported its taxonomic affiliation as a novel species of the Bacillus genus, for which the name Bacillus rugosus sp. nov. is proposed. The type strain is SPB7 (= NRRL B-65559, = CICC 24827, = MCC 4185).
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http://dx.doi.org/10.1007/s10482-020-01472-9DOI Listing
November 2020

Patient-derived cells from recurrent tumors that model the evolution of -mutant glioma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa088. Epub 2020 Jul 16.

Department of Neurological Surgery, University of California, San Francisco, California, USA.

Background: mutant lower-grade gliomas (LGGs) evolve under the selective pressure of therapy, but well-characterized patient-derived cells (PDCs) modeling evolutionary stages are lacking. -mutant LGGs may develop therapeutic resistance associated with chemotherapy-driven hypermutation and malignant progression. The aim of this study was to establish and characterize PDCs, single-cell-derived PDCs (scPDCs), and xenografts (PDX) of -mutant recurrences representing distinct stages of tumor evolution.

Methods: We derived and validated cell cultures from mutant recurrences of astrocytoma and oligodendroglioma. We used exome sequencing and phylogenetic reconstruction to examine the evolutionary stage represented by PDCs, scPDCs, and PDX relative to corresponding spatiotemporal tumor tissue and germline DNA. PDCs were also characterized for growth and tumor immortality phenotypes, and PDX were examined histologically.

Results: The integrated astrocytoma phylogeny revealed 2 independent founder clonal expansions of hypermutated (HM) cells in tumor tissue that are faithfully represented by independent PDCs. The oligodendroglioma phylogeny showed more than 4000 temozolomide-associated mutations shared among tumor samples, PDCs, scPDCs, and PDX, suggesting a shared monoclonal origin. The PDCs from both subtypes exhibited hallmarks of tumorigenesis, retention of subtype-defining genomic features, production of 2-hydroxyglutarate, and subtype-specific telomere maintenance mechanisms that confer tumor cell immortality. The oligodendroglioma PDCs formed infiltrative intracranial tumors with characteristic histology.

Conclusions: These PDCs, scPDCs, and PDX are unique and versatile community resources that model the heterogeneous clonal origins and functions of recurrent -mutant LGGs. The integrated phylogenies advance our knowledge of the complex evolution and immense mutational load of -mutant HM glioma.
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http://dx.doi.org/10.1093/noajnl/vdaa088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462278PMC
July 2020

Assessment of polycyclic aromatic hydrocarbon contamination in the Sundarbans, the world's largest tidal mangrove forest and indigenous microbial mixed biofilm-based removal of the contaminants.

Environ Pollut 2020 Nov 6;266(Pt 1):115270. Epub 2020 Aug 6.

School of Environmental Studies, Jadavpur University, Kolkata, 700032, India. Electronic address:

The distribution of polycyclic aromatic hydrocarbons (PAHs) in the surface water and sediments in five regions of the Indian Sundarbans was assessed. The capability of microbial biofilm communities to sequester PAHs in a biofilm-promoting vessel was evaluated. The total PAH concentration of water and sediments ranged from undetectable to 125 ng ml and 4880 to 2 × 10 ng g dry weight respectively. The total PAHs concentration of sediments exceeded the Effects Range-Low value and the recommended Effects Range-Median values, implying the PAHs might adversely affect the biota of the Sundarbans. Pyrogenic and petrogenic sources of PAH contamination were identified in most of the sampling sites. Indigenous biofilms were cultivated in a patented biofilm-promoting culture vessel containing liquid media spiked with 16 priority PAHs. Biofilm-mediated 97-100% removal efficiency of 16 PAHs was attained in all media. There was no significant difference between the mean residual PAH from the liquid media collected from hydrophobic and hydrophilic flasks. Residual amounts of acenaphthene (Ace), anthracene (Ant), benzo(b)fluoranthene [B(b)F], benzo(a)pyrene [B(a)P] and benzo(g,h,i)perylene [B(g,h,i)P] showed differences when cultivated in hydrophobic and hydrophilic flasks. The mean residual amounts of total PAHs extracted from biofilm biomasses were variable. A biofilm obtained from a specific sampling site cultured in the hydrophobic flask showed higher PAH sequestration when compared to the removal attained in the hydrophilic flask. Relative abundances of different microbial communities in PAH-sequestering biofilms revealed bacterial phyla including Proteobacteria, Bacteroidetes, Firmicutes, Actinobacteria, Chloroflexi and Planctomycetes as well as members of Ascomycota phylum of fungi. The dominance of Candida tropicalis, Clostridium butyricum, Sphingobacterium multivorum and Paecilomyces fulvus were established.
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http://dx.doi.org/10.1016/j.envpol.2020.115270DOI Listing
November 2020

Draft Genome Sequence of sp. Strain SPB7, Isolated from the Marine Sponge Spongia officinalis.

Microbiol Resour Announc 2020 Jul 23;9(30). Epub 2020 Jul 23.

School of Environmental Studies, Jadavpur University, Kolkata, India

The draft genome of sp. SPB7, which was isolated from the marine sponge , is presented. This bacterium is a producer of an antimicrobial cyclic diketopiperazine, (3,6)-3,6-diisobutylpiperazine-2,5-dione. The genome consists of 4,511 protein-coding genes, 63 tRNAs, 2 16S rRNAs, 3 23S rRNAs, and a single copy of 5S rRNA.
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http://dx.doi.org/10.1128/MRA.00358-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378024PMC
July 2020

Phosphoglycerate Mutase 1 Activates DNA Damage Repair via Regulation of WIP1 Activity.

Cell Rep 2020 04;31(2):107518

Department of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address:

The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) is overexpressed in several types of cancer, suggesting an additional function beyond its established role in the glycolytic pathway. We here report that PGAM1 is overexpressed in gliomas where it increases the efficiency of the DNA damage response (DDR) pathway by cytoplasmic binding of WIP1 phosphatase, thereby preventing WIP1 nuclear translocation and subsequent dephosphorylation of the ATM signaling pathway. Silencing of PGAM1 expression in glioma cells consequently decreases formation of γ-H2AX foci, increases apoptosis, and decreases clonogenicity following irradiation (IR) and temozolomide (TMZ) treatment. Furthermore, mice intracranially implanted with PGAM1-knockdown cells have significantly improved survival after treatment with IR and TMZ. These effects are counteracted by exogenous expression of two kinase-dead PGAM1 mutants, H186R and Y92F, indicating an important non-enzymatic function of PGAM1. Our findings identify PGAM1 as a potential therapeutic target in gliomas.
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http://dx.doi.org/10.1016/j.celrep.2020.03.082DOI Listing
April 2020

The Correlation of Fluorescence of Protoporphyrinogen IX and Status of Isocitrate Dehydrogenase in Gliomas.

Neurosurgery 2020 08;87(2):408-417

Department of Neurosurgery, Fujita Health University, Toyoake, Japan.

Background: The extent of resection has been reported to be associated with overall survival in gliomas. The use of 5-aminolevulinic acid (5-ALA) has been recognized to increase the extent of tumor resection.

Objective: To evaluate what factors affect the intraoperative fluorescence after administration of 5-ALA in gliomas.

Methods: Correlation of intraoperative fluorescence and several clinical, radiographic, molecular biologic, and histopathologic characters was retrospectively evaluated in 104 patients (53 males and 51 females; mean age 54.2 yr) with gliomas at our institution. To clarify the mechanisms that mutant isocitrate dehydrogenase (IDH) affect the intraoperative fluorescence, in Vitro experiments using genetically engineered glioma cells harboring mutant IDH1 were performed.

Results: Intraoperative fluorescence was observed in 82 patients (78.8%). In addition to age, magnetic resonance imaging enhancement, World Health Organization grades, and MIB-1 index, the status of IDH was revealed to be correlated with intraoperative fluorescence. In Vitro assay revealed that mutant IDH indirectly reduced the amount of exogenous 5-ALA-derived protoporphyrinogen IX in glioma cells by increasing activity of ferrochelatase and heme oxygenase 1.

Conclusion: Mutant IDH1/2-induced metabolite changes of exogenous 5-ALA were suggested to contribute to the lesser intraoperative fluorescence in gliomas with mutant IDH1/2 than in those without.
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http://dx.doi.org/10.1093/neuros/nyz524DOI Listing
August 2020

Structural elucidation and antimicrobial activity of a diketopiperazine isolated from a sp. associated with the marine sponge .

Nat Prod Res 2021 Jul 4;35(14):2315-2323. Epub 2019 Oct 4.

School of Environmental Studies, Jadavpur University , Kolkata , India.

A diketopiperazine (3, 6)-3,6-diisobutylpiperazine-2,5-dione was isolated from a sponge-associated microbe for the first time and characterized by FTIR, HRESI-MS, H, C NMR and 2D NMR. The source is novel for this compound. Single crystal XRD of this diketopiperazine obtained as a natural product was analysed for the first time and its melting point was determined to be 262 °C. MICs of this cyclic dipeptide against and were 16 µg mL and 22 µg mL respectively, the first report of antibacterial activity of this diketopiperazine.Supplemental data for this article can be accessed at https://doi.org/10.1080/14786419.2019.1672684.
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http://dx.doi.org/10.1080/14786419.2019.1672684DOI Listing
July 2021

Removal of Pb (II), As (III), and Cr (VI) by nitrogen-starved Papiliotrema laurentii strain RY1.

J Basic Microbiol 2019 Oct 20;59(10):1016-1030. Epub 2019 Aug 20.

Department of Life Science and Biotechnology, Jadavpur University, Kolkata, India.

Heavy metals such as lead, chromium, and metalloid like arsenic dominate the pinnacle in posing a threat to life. Being environment-friendly, elucidating the mechanism by which microorganisms detoxify such elements has always been an active field of research hitherto. In the present study, we have investigated the capability of nitrogen-deprived Papiliotrema laurentii strain RY1 toward enhanced tolerance and neutralizing toxic elements. There were biosorption and bioprecipitation of lead and chromium at the cell surfaces. Bioprecipitation mechanisms included the formation of lead phosphates and pyromorphites from lead, grimaldite from chromium. Transcripts such as metallothionein, aquaporins, and arsenical pump-driving ATPase have been surmised to be involved in the detoxification of elements. Furthermore, activation of antioxidant defense mechanisms for the cells for each of the elements should contribute towards yeast's propagation. The efficiency of removal of elements for live cells and immobilized cells were high for lead and chromium. To the best of our knowledge, this is the first report of such high tolerance of lead, arsenic, and chromium for any yeast. The yeast showed such varied response under dual stress due to nitrogen starvation and in the presence of respective elements. The yeast possesses promising potentials in nitrogen deprived and enriched environments to aid in bioremediation sectors.
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http://dx.doi.org/10.1002/jobm.201900222DOI Listing
October 2019

Monitoring of biofilms grown on differentially structured metallic surfaces using confocal laser scanning microscopy.

Eng Life Sci 2019 Jul 21;19(7):513-521. Epub 2019 May 21.

Institute of Bioprocess Engineering TU Kaiserslautern Kaiserslautern Germany.

Imaging of biofilms on opaque surfaces is a challenge presented to researchers especially considering pathogenic bacteria, as those typically grow on living tissue, such as mucosa and bone. However, they can also grow on surfaces used in industrial applications such as food production, acting as a hindrance to the process. Thus, it is important to understand bacteria better in the environment they actually have relevance in. Stainless steel and titanium substrata were line structured and dotted surface topographies for titanium substrata were prepared to analyze their effects on biofilm formation of a constitutively green fluorescent protein (GFP)-expressing strain. The strain was batch cultivated in a custom built flow cell initially for 18 h, followed by continuous cultivation for 6 h. Confocal laser scanning microscopy (CLSM) was used to determine the biofilm topography. Biofilm growth of GFPmut2 was not affected by the type of metal substrate used; rather, attachment and growth were influenced by variable shapes of the microstructured titanium surfaces. In this work, biofilm cultivation in flow cells was coupled with the most widely used biofilm analytical technique (CLSM) to study the time course of growth of a GFP-expressing biofilm on metallic surfaces without intermittent sampling or disturbing the natural development of the biofilm.
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http://dx.doi.org/10.1002/elsc.201800176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6999451PMC
July 2019

Mutant and Wild-Type Isocitrate Dehydrogenase 1 Share Enhancing Mechanisms Involving Distinct Tyrosine Kinase Cascades in Cancer.

Cancer Discov 2019 06 12;9(6):756-777. Epub 2019 Mar 12.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.

Isocitrate dehydrogenase 1 (IDH1) is important for reductive carboxylation in cancer cells, and the IDH1 R132H mutation plays a pathogenic role in cancers including acute myeloid leukemia (AML). However, the regulatory mechanisms modulating mutant and/or wild-type (WT) IDH1 function remain unknown. Here, we show that two groups of tyrosine kinases (TK) enhance the activation of mutant and WT IDH1 through preferential Y42 or Y391 phosphorylation. Mechanistically, Y42 phosphorylation occurs in IDH1 monomers, which promotes dimer formation with enhanced substrate (isocitrate or α-ketoglutarate) binding, whereas Y42-phosphorylated dimers show attenuated disruption to monomers. Y391 phosphorylation occurs in both monomeric and dimeric IDH1, which enhances cofactor (NADP or NADPH) binding. Diverse oncogenic TKs phosphorylate IDH1 WT at Y42 and activate Src to phosphorylate IDH1 at Y391, which contributes to reductive carboxylation and tumor growth, whereas FLT3 or the FLT3-ITD mutation activates JAK2 to enhance mutant IDH1 activity through phosphorylation of Y391 and Y42, respectively, in AML cells. SIGNIFICANCE: We demonstrated an intrinsic connection between oncogenic TKs and activation of WT and mutant IDH1, which involves distinct TK cascades in related cancers. In particular, these results provide an additional rationale supporting the combination of FLT3 and mutant IDH1 inhibitors as a promising clinical treatment of mutant IDH1-positive AML...
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http://dx.doi.org/10.1158/2159-8290.CD-18-1040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6548588PMC
June 2019

HDAC inhibition in glioblastoma monitored by hyperpolarized C MRSI.

NMR Biomed 2019 02 18;32(2):e4044. Epub 2018 Dec 18.

Department of Radiology and Biomedical Imaging, University of California San Francisco, San Francisco, CA, USA.

Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM models. First, we confirmed HDAC inhibition in U87 GBM cells and evaluated real-time dynamic metabolic changes using a bioreactor system with live vorinostat-treated or control cells. We found a significant 40% decrease in the C MRS-detectable ratio of hyperpolarized [1- C]lactate to hyperpolarized [1- C]pyruvate, [1- C]Lac/Pyr, and a 37% decrease in the pseudo-rate constant, k , for hyperpolarized [1- C]lactate production, in vorinostat-treated cells compared with controls. To understand the underlying mechanism for this finding, we assessed the expression and activity of lactate dehydrogenase (LDH) (which catalyzes the pyruvate to lactate conversion), its associated cofactor nicotinamide adenine dinucleotide, the expression of monocarboxylate transporters (MCTs) MCT1 and MCT4 (which shuttle pyruvate and lactate in and out of the cell) and intracellular lactate levels. We found that the most likely explanation for our finding that hyperpolarized lactate is reduced in treated cells is a 30% reduction in intracellular lactate levels that occurs as a result of increased expression of both MCT1 and MCT4 in vorinostat-treated cells. In vivo C MRSI studies of orthotopic tumors in mice also showed a significant 52% decrease in hyperpolarized [1- C]Lac/Pyr when comparing vorinostat-treated U87 GBM tumors with controls, and, as in the cell studies, this metabolic finding was associated with increased MCT1 and MCT4 expression in HDAC-inhibited tumors. Thus, the C MRSI-detectable decrease in hyperpolarized [1- C]lactate production could serve as a biomarker of response to HDAC inhibitors.
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http://dx.doi.org/10.1002/nbm.4044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545173PMC
February 2019

U32 collagenase from Pseudoalteromonas agarivorans NW4327: Activity, structure, substrate interactions and molecular dynamics simulations.

Int J Biol Macromol 2019 Mar 23;124:635-650. Epub 2018 Nov 23.

School of Environmental Studies, Jadavpur University, Kolkata 700 032, India. Electronic address:

A protease of the primary pathogen (Pseudoalteromonas agarivorans NW4327) of the disease affecting the Great Barrier Reef sponge Rhopaloeides odorabile was purified. Zymography demonstrated calcium-dependent collagenase and gelatinase activity of the purified protein. This metalloprotease was identified by matrix assisted laser desorption ionization time-of-flight mass spectrophotometry as a 52,509 Da U32 collagenase. Predicted tertiary structure of U32 collagenase (by Phyre2 fold recognition server) demonstrated 13% identity with known hydrolases establishing novelty of the enzyme. Molecular docking conceived two interacting loops of the collagenase that bound with collagen triple helices and two calcium ions remained centered between the loops. According to ConSurf multiple sequence alignment, the residues of loop1 of the collagenase were mostly conserved while variations among residues of loop2 were comparatively higher than loop1. Asp262, Glu263 of loop1 and Thr363, Lys364, Gln365 of loop2 participated in the interaction with Ca and collagen. Root mean square deviation and root mean square fluctuation values signified higher stability of the collagen-Ca-collagenase complex and greater structural stability of the residues of the loops in the complex compared to apocollagenase. Observed properties of NW4327 U32 collagenase and its interaction with collagen were different from similar enzymes of thermophilic bacteria and terrestrial pathogens.
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http://dx.doi.org/10.1016/j.ijbiomac.2018.11.206DOI Listing
March 2019

Neurofibromin knockdown in glioma cell lines is associated with changes in cytokine and chemokine secretion in vitro.

Sci Rep 2018 04 11;8(1):5805. Epub 2018 Apr 11.

Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.

The neurofibromin-1 tumor suppressor gene (NF1) is altered in approximately 20% of sporadic glioblastoma (GBM) cases. NF1 deficient GBM frequently shows a mesenchymal gene expression signature, suggesting a relationship between NF1 status and the tumor microenvironment. To identify changes in the production of secreted cytokines/chemokines in NF1 deficient glioma, we applied cytokine arrays to conditioned media from a panel of three GBM cell lines after siRNA-mediated NF1 knockdown. We identified increased secretion of platelet-derived growth factor AA (PDGF-AA), chitinase-3-like protein 1 (CHI3L1), interleukin-8 (IL-8), and endoglin (ENG) in different subsets of these cell lines. Secretion was associated with induction of the corresponding messenger RNA, suggesting a mechanism involving transcriptional upregulation. By contrast, in non-transformed immortalized normal human astrocytes, PDGF-AA secretion was increased upon NF1 knockdown, while secreted CHI3L1, ENG, and IL-8 were reduced or unchanged. Analysis of The Cancer Genome Atlas confirmed a relationship between glioma NF1 status and ENG and CHI3L1 in tumor samples. Overall, this study identifies candidate changes in secreted proteins from NF1 deficient glioma cells that could influence the tumor microenvironment, and suggests a direct link between NF1 loss and increased tumor cell production of CHI3L1 and endoglin, two factors implicated in mesenchymal identity in glioblastoma.
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http://dx.doi.org/10.1038/s41598-018-24046-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895785PMC
April 2018

Mutant IDH1 Cooperates with ATRX Loss to Drive the Alternative Lengthening of Telomere Phenotype in Glioma.

Cancer Res 2018 06 15;78(11):2966-2977. Epub 2018 Mar 15.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

A subset of tumors use a recombination-based alternative lengthening of telomere (ALT) pathway to resolve telomeric dysfunction in the absence of TERT. Loss-of-function mutations in the chromatin remodeling factor ATRX are associated with ALT but are insufficient to drive the process. Because many ALT tumors express the mutant isocitrate dehydrogenase IDH1 R132H, including all lower grade astrocytomas and secondary glioblastoma, we examined a hypothesized role for IDH1 R132H in driving the ALT phenotype during gliomagenesis. In p53/pRb-deficient human astrocytes, combined deletion of ATRX and expression of mutant IDH1 were sufficient to create tumorigenic cells with ALT characteristics. The telomere capping complex component RAP1 and the nonhomologous DNA end joining repair factor XRCC1 were each downregulated consistently in these tumorigenic cells, where their coordinate reexpression was sufficient to suppress the ALT phenotype. RAP1 or XRCC1 downregulation cooperated with ATRX loss in driving the ALT phenotype. RAP1 silencing caused telomere dysfunction in ATRX-deficient cells, whereas XRCC1 silencing suppressed lethal fusion of dysfunctional telomeres by allowing IDH1-mutant ATRX-deficient cells to use homologous recombination and ALT to resolve telomeric dysfunction and escape cell death. Overall, our studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis. Studies show how expression of mutant IDH1 initiates telomeric dysfunction and alters DNA repair pathway preferences at telomeres, cooperating with ATRX loss to defeat a key barrier to gliomagenesis and suggesting new therapeutic options to treat low-grade gliomas. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-2269DOI Listing
June 2018

A new collagenase enzyme of the marine sponge pathogen Pseudoalteromonas agarivorans NW4327 is uniquely linked with a TonB dependent receptor.

Int J Biol Macromol 2018 Apr 20;109:1140-1146. Epub 2017 Nov 20.

School of Environmental Studies, Jadavpur University, Kolkata, 700032, India. Electronic address:

The primary pathogen of the Great Barrier Reef sponge Rhopaloeides odorabile, recently identified as a novel strain (NW4327) of Pseudoalteromonas agarivorans, produced collagenase which degraded R. odorabile skeletal fibers. We now report the collagenase of P. agarivorans as a metalloprotease which required Ca and Zn as cofactors. The collagenase was a TonB dependent receptor (TBDR) having a carboxypeptidase regulatory like domain (CRLD) in the N-terminal along with an outer membrane (OM) channel superfamily domain. The genes for TBDR sub-components and collagenase formed one unified entity in the genome of P. agarivorans NW4327. This association of a collagenase with a TBDR distinguished it from all known functional collagenases till date and for the first time, established the enzymatic capability of TBDRs. Predicted TBDR model demonstrated only 15% identity with ferripyoverdin receptor and the CRLD displayed merely 24% identity with carboxypeptidase catalytic chain. Presence of signal peptide, lack of transmembrane helices, absence of N-terminal in the cytoplasmic side, extracellular localization and recovery from the culture supernatant implicated that the TBDR was secreted. Stronger binding of the collagenase with marine sponge type IV collagen than type I collagen, revealed through molecular docking, indicated higher specificity of the enzyme towards type IV collagen.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.11.106DOI Listing
April 2018

Production enhancement and characterization of the polyhydroxyalkanoate produced by Natrinema ajinwuensis (as synonym) ≡ Natrinema altunense strain RM-G10.

Int J Biol Macromol 2018 Feb 5;107(Pt B):1480-1490. Epub 2017 Oct 5.

School of Environmental Studies, Jadavpur University, Kolkata 700 032, India. Electronic address:

Application of halophiles can decrease the cost of polyhydroxyalkanoate (PHA) production or bioplastic which are an alternative to the petroleum-derived plastic. Extremely halophilic archaeon, Natrinema ajinwuensis RM-G10 accumulated 61.02±0.68% PHA of its cell dry mass at 72h in repeated batch cultures yielding 0.210±0.001gLh volumetric productivity after selection of the best cultivation conditions. Transmission electron microscopy showed the presence of PHA granules inside the archaeal cells. Characterization by gas chromatographic analysis, gas chromatographic- mass spectrophotometric analysis, thermogravimetric analysis, differential scanning calorimetric analysis, X-ray diffraction analysis, Fourier transform infra red spectroscopy and nuclear magnetic resonance spectroscopy revealed the polymer to be poly(3-hydroxybutyrate-co-3-hydroxyvalerate) with 13.93mol% 3-hydroxyvalerate content and having 35.45% crystallinity, -12.3°C glass transition temperature, 143°C and 157.5°C melting temperatures and 284°C degradation temperature. This is the first report on production enhancement (on a small scale) and characterization of the polyhydroxyalkanoate produced by Natrinema ajinwuensis (as synonym) ≡ Natrinema altunense strain RM-G10 and the Natrinema genus in general.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.10.009DOI Listing
February 2018

Recent Drug Resistant Epilepsy Spectrum in Eastern India.

J Epilepsy Res 2017 Jun 30;7(1):39-44. Epub 2017 Jun 30.

Department of Neurology, NRS Medical College Hospital, Kolkata, India.

Background And Purpose: The Magnitude of Drug-resistant Epilepsy (DRE) in India, being unknown, takes a heavy toll on the patients and society in the form of prolonged dependence, unemployment, morbidity and mortality. We tried to explore the clinical, electro-physiological, neuro-imaging and drug-response spectrum of DRE patients in Eastern India in our study.

Methods: During the period of January 2014 to December 2015, epilepsy patients were treated and DRE patients were identified according to International League Against Epilepsy criteria. We isolated those patients and studied them in a special clinic.

Results: Among 2,153 patients treated in Neurology out-patient department, 243 (11.3%) patients were drug-resistant. Among the DRE patients, 63% were male. Age-wise 40%, 30.5% & 18.1% patients were presented in their first, second and third decades respectively. Males were more affected in 0-5 years age group while females in 6-10 years age group. Various seizures types were found alone or in combination. Males were mostly affected by generalized tonic clonic seizure and myoclonus and females by complex partial seizure. Positive family history was higher in partial seizure group. Electroencephalographic (EEG) abnormalities were common with structural lesions in brain. EEG findings in different etiologies were varied with a large number of DRE patients who were found to have normal EEG. Females were higher medicine non-compliant.

Conclusions: The spectrum was pointed towards gender predilection for specific age group and also for seizure types. Idiopathic cases were most common in DRE, pointing towards the need of newer investigations. Normal EEG could be found even in a DRE patient. Non-compliance was more in females.
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http://dx.doi.org/10.14581/jer.17007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540689PMC
June 2017

Streptomyces euryhalinus sp. nov., a new actinomycete isolated from a mangrove forest.

J Antibiot (Tokyo) 2017 Jun 8;70(6):747-753. Epub 2017 Feb 8.

School of Environmental Studies, Jadavpur University, Kolkata, India.

A Gram-positive, aerobic, non-motile actinomycete (strain MS 3/20) was isolated from the sediment of the Sundarbans mangrove forest in India. On International Streptomyces Project (ISP) medium 2, the isolate produced yellowish brown to red aerial hyphae that carried spiny-surfaced spores in a retinaculum-apertum arrangement. Whole-cell hydrolysate of the strain contained LL-diaminopimelic acid and galactose. Predominant menaquinones were MK-9(H) and MK-9(H). Diagnostic polar lipids were glycolipid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, unidentified phospholipid and unidentified amino lipid. The major fatty acids were anteiso-C (17.53%), iso-C (23.89%) and anteiso-C (10.29%). The strain showed 100% 16S ribosomal RNA (rRNA) gene sequence similarity with Streptomyces variabilis NBRC 12825, Streptomyces erythrogriseus LMG 19406, Streptomyces griseoincarnatus LMG 19316 and Streptomyces labedae NBRC 15864. However, strain MS 3/20 could be distinguished from these and seven other closely related species based on low levels of DNA-DNA relatedness (27.2-53.8%), supported by the unique banding pattern obtained from random amplified polymorphic DNA-PCR amplification and the distinctive matrix-assisted laser desorption/ionization-time-of-flight/mass spectrometry (MALDI-TOF/MS) profile of whole-cell proteins acquired for strain MS 3/20 in comparison with its phylogenetic relatives. Disparate morphological, physiological and chemotaxonomic features, principally growth in NaCl, further corroborated the distinction of strain MS 3/20 from other phylogenetic relatives. Strain MS 3/20 is therefore suggested to be a novel species of the genus Streptomyces, for which the name Streptomyces euryhalinus sp. nov. is proposed. The type strain is MS 3/20 (=CICC 11032=DSM 103378).
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http://dx.doi.org/10.1038/ja.2017.3DOI Listing
June 2017

Mutant IDH1 Expression Drives TERT Promoter Reactivation as Part of the Cellular Transformation Process.

Cancer Res 2016 11 6;76(22):6680-6689. Epub 2016 Oct 6.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Mutations in the isocitrate dehydrogenase gene IDH1 are common in low-grade glioma, where they result in the production of 2-hydroxyglutarate (2HG), disrupted patterns of histone methylation, and gliomagenesis. IDH1 mutations also cosegregate with mutations in the ATRX gene and the TERT promoter, suggesting that IDH mutation may drive the creation or selection of telomere-stabilizing events as part of immortalization/transformation process. To determine whether and how this may occur, we investigated the phenotype of pRb-/p53-deficient human astrocytes engineered with IDH1 wild-type (WT) or R132H-mutant (IDH1) genes as they progressed through their lifespan. IDH1 expression promoted 2HG production and altered histone methylation within 20 population doublings (PD) but had no effect on telomerase expression or telomere length. Accordingly, cells expressing either IDH1 or IDH1 entered a telomere-induced crisis at PD 70. In contrast, only IDH1 cells emerged from crisis, grew indefinitely in culture, and formed colonies in soft agar and tumors in vivo Clonal populations of postcrisis IDH1 cells displayed shared genetic alterations, but no mutations in ATRX or the TERT promoter were detected. Instead, these cells reactivated telomerase and stabilized their telomeres in association with increased histone lysine methylation (H3K4me3) and c-Myc/Max binding at the TERT promoter. Overall, these results show that although IDH1 does not create or select for ATRX or TERT promoter mutations, it can indirectly reactivate TERT, and in doing so contribute to astrocytic immortalization and transformation. Cancer Res; 76(22); 6680-9. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290072PMC
November 2016

Rapid Conversion of Mutant IDH1 from Driver to Passenger in a Model of Human Gliomagenesis.

Mol Cancer Res 2016 10 18;14(10):976-983. Epub 2016 Jul 18.

Department of Neurological Surgery, University of California, San Francisco, San Francisco, California.

Missense mutations in the active site of isocitrate dehydrogenase 1 (IDH1) biologically and diagnostically distinguish low-grade gliomas and secondary glioblastomas from primary glioblastomas. IDH1 mutations lead to the formation of the oncometabolite 2-hydroxyglutarate (2-HG) from the reduction of α-ketoglutarate (α-KG), which in turn facilitates tumorigenesis by modifying DNA and histone methylation as well blocking differentiation processes. Although mutant IDH1 expression is thought to drive the gliomagenesis process, the extent to which it remains a viable therapeutic target remains unknown. To address this question, we exposed immortalized (p53/pRb deficient), untransformed human astrocytes to the mutant IDH1 inhibitor AGI-5198 prior to, concomitant with, or at intervals after, introduction of transforming mutant IDH1, then measured effects on 2-HG levels, histone methylation (H3K4me3, H3K9me2, H3K9me3, or H3K27me3), and growth in soft agar. Addition of AGI-5198 prior to, or concomitant with, introduction of mutant IDH1 blocked all mutant IDH1-driven changes, including cellular transformation. Addition at time intervals as short as 4 days following introduction of mutant IDH1 also suppressed 2-HG levels, but had minimal effects on histone methylation, and lost the ability to suppress clonogenicity in a time-dependent manner. Furthermore, in two different models of mutant IDH1-driven gliomagenesis, AGI-5198 exposures that abolished production of 2-HG also failed to decrease histone methylation, adherent cell growth, or anchorage-independent growth in soft agar over a prolonged period. These studies show although mutant IDH1 expression drives gliomagenesis, mutant IDH1 itself rapidly converts from driver to passenger.

Implications: Agents that target mutant IDH may be effective for a narrow time and may require further optimization or additional therapeutics in glioma. Mol Cancer Res; 14(10); 976-83. ©2016 AACR.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5065766PMC
http://dx.doi.org/10.1158/1541-7786.MCR-16-0141DOI Listing
October 2016

PKM2 uses control of HuR localization to regulate p27 and cell cycle progression in human glioblastoma cells.

Int J Cancer 2016 Jul 2;139(1):99-111. Epub 2016 Mar 2.

The Department of Neurological Surgery and the Brain Tumor Research Center, Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, CA, 94158.

The M2 isoform of pyruvate kinase (PK) is upregulated in most cancers including glioblastoma. Although PKM2 has been reported to use dual kinase activities to regulate cell growth, it also interacts with phosphotyrosine (pY)-containing peptides independently of its kinase activity. The potential for PKM2 to use the binding of pY-containing proteins to control tumor growth has not been fully examined. We here describe a novel mechanism by which PKM2 interacts in the nucleus with the RNA binding protein HuR to regulate HuR sub-cellular localization, p27 levels, cell cycle progression and glioma cell growth. Suppression of PKM2 in U87, T98G and LN319 glioma cells resulted in increased p27 levels, defects in entry into mitosis, increased centrosome number, and decreased cell growth. These effects could be reversed by shRNA targeting p27. The increased levels of p27 in PKM2 knock-down cells were caused by a loss of the nuclear interaction between PKM2 and HuR, and a subsequent cytoplasmic re-distribution of HuR, which in turn led to increased cap-independent p27 mRNA translation. Consistent with these results, the alterations in p27 mRNA translation, cell cycle progression and cell growth caused by PKM2 suppression could be reversed in vitro and in vivo by suppression of HuR or p27 levels, or by introduction of forms of PKM2 that could bind pY, regardless of their kinase activity. These results define a novel mechanism by which PKM2 regulates glioma cell growth, and also define a novel set of potential therapeutic targets along the PKM2-HuR-p27 pathway.
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http://dx.doi.org/10.1002/ijc.30041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615049PMC
July 2016
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