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  • 1
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    Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha (1999)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1999-01-15
    Description: Phosphoinositide 3-kinase (PI3K) activation has been implicated in many cellular responses, including fibroblast growth, transformation, survival, and chemotaxis. Although PI3K is activated by several agents that stimulate T and B cells, the role of PI3K in lymphocyte function is not clear. The mouse gene encoding the PI3K adapter subunit p85alpha and its splice variants p55alpha and p50alpha was disrupted. Most p85alpha-p55alpha-p50alpha-/- mice die within days after birth. Lymphocyte development and function was studied with the use of the RAG2-deficient blastocyst complementation system. Chimeric mice had reduced numbers of peripheral mature B cells and decreased serum immunoglobulin. The B cells that developed had diminished proliferative responses to antibody to immunoglobulin M, antibody to CD40, and lipopolysaccharide stimulation and decreased survival after incubation with interleukin-4. In contrast, T cell development and proliferation was normal. This phenotype is similar to defects observed in mice lacking the tyrosine kinase Btk.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Fruman, D A -- Snapper, S B -- Yballe, C M -- Davidson, L -- Yu, J Y -- Alt, F W -- Cantley, L C -- R01 GM041890/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 1999 Jan 15;283(5400):393-7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dfruman@bidmc.harvard.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9888855" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antigens, CD45/analysis ; Apoptosis ; B-Lymphocytes/cytology/enzymology/*immunology ; Catalytic Domain ; Cell Cycle ; Chimera ; Chromones/pharmacology ; Enzyme Inhibitors/pharmacology ; Female ; Gene Targeting ; Immunoglobulins/*blood ; *Lymphocyte Activation ; Lymphocyte Count ; Male ; Mice ; Mice, Inbred C57BL ; Morpholines/pharmacology ; Phosphatidylinositol 3-Kinases/antagonists & inhibitors/genetics/*metabolism ; Protein-Tyrosine Kinases/genetics/metabolism ; Spleen/immunology ; T-Lymphocytes/cytology/enzymology/immunology
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 2
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    The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth (2008)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2008-03-14
    Description: Many tumour cells have elevated rates of glucose uptake but reduced rates of oxidative phosphorylation. This persistence of high lactate production by tumours in the presence of oxygen, known as aerobic glycolysis, was first noted by Otto Warburg more than 75 yr ago. How tumour cells establish this altered metabolic phenotype and whether it is essential for tumorigenesis is as yet unknown. Here we show that a single switch in a splice isoform of the glycolytic enzyme pyruvate kinase is necessary for the shift in cellular metabolism to aerobic glycolysis and that this promotes tumorigenesis. Tumour cells have been shown to express exclusively the embryonic M2 isoform of pyruvate kinase. Here we use short hairpin RNA to knockdown pyruvate kinase M2 expression in human cancer cell lines and replace it with pyruvate kinase M1. Switching pyruvate kinase expression to the M1 (adult) isoform leads to reversal of the Warburg effect, as judged by reduced lactate production and increased oxygen consumption, and this correlates with a reduced ability to form tumours in nude mouse xenografts. These results demonstrate that M2 expression is necessary for aerobic glycolysis and that this metabolic phenotype provides a selective growth advantage for tumour cells in vivo.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Christofk, Heather R -- Vander Heiden, Matthew G -- Harris, Marian H -- Ramanathan, Arvind -- Gerszten, Robert E -- Wei, Ru -- Fleming, Mark D -- Schreiber, Stuart L -- Cantley, Lewis C -- R01 GM056203/GM/NIGMS NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2008 Mar 13;452(7184):230-3. doi: 10.1038/nature06734.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18337823" target="_blank"〉PubMed〈/a〉
    Keywords: Alternative Splicing/*genetics ; Animals ; Cell Line, Tumor ; Cell Proliferation ; Fructosediphosphates/metabolism ; Gene Expression Regulation, Neoplastic ; Glycolysis ; Humans ; Lactic Acid/metabolism ; Lung Neoplasms/genetics/metabolism/pathology ; Male ; Mice ; Mice, Nude ; Neoplasm Transplantation ; Neoplasms/enzymology/genetics/*metabolism/*pathology ; Oxidative Phosphorylation ; Oxygen Consumption ; Pyruvate Kinase/*genetics/*metabolism ; Pyruvic Acid/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 3
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    Evidence for an alternative glycolytic pathway in rapidly proliferating cells (2010)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2010-09-18
    Description: Proliferating cells, including cancer cells, require altered metabolism to efficiently incorporate nutrients such as glucose into biomass. The M2 isoform of pyruvate kinase (PKM2) promotes the metabolism of glucose by aerobic glycolysis and contributes to anabolic metabolism. Paradoxically, decreased pyruvate kinase enzyme activity accompanies the expression of PKM2 in rapidly dividing cancer cells and tissues. We demonstrate that phosphoenolpyruvate (PEP), the substrate for pyruvate kinase in cells, can act as a phosphate donor in mammalian cells because PEP participates in the phosphorylation of the glycolytic enzyme phosphoglycerate mutase (PGAM1) in PKM2-expressing cells. We used mass spectrometry to show that the phosphate from PEP is transferred to the catalytic histidine (His11) on human PGAM1. This reaction occurred at physiological concentrations of PEP and produced pyruvate in the absence of PKM2 activity. The presence of histidine-phosphorylated PGAM1 correlated with the expression of PKM2 in cancer cell lines and tumor tissues. Thus, decreased pyruvate kinase activity in PKM2-expressing cells allows PEP-dependent histidine phosphorylation of PGAM1 and may provide an alternate glycolytic pathway that decouples adenosine triphosphate production from PEP-mediated phosphotransfer, allowing for the high rate of glycolysis to support the anabolic metabolism observed in many proliferating cells.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030121/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3030121/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Vander Heiden, Matthew G -- Locasale, Jason W -- Swanson, Kenneth D -- Sharfi, Hadar -- Heffron, Greg J -- Amador-Noguez, Daniel -- Christofk, Heather R -- Wagner, Gerhard -- Rabinowitz, Joshua D -- Asara, John M -- Cantley, Lewis C -- 1K08CA136983/CA/NCI NIH HHS/ -- 1P01CA120964-01A/CA/NCI NIH HHS/ -- 5 T32 CA009361-28/CA/NCI NIH HHS/ -- 5P30CA006516-43/CA/NCI NIH HHS/ -- K08 CA136983/CA/NCI NIH HHS/ -- K08 CA136983-02/CA/NCI NIH HHS/ -- P01 CA089021/CA/NCI NIH HHS/ -- P01 CA089021-10/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P01 CA120964-01A1/CA/NCI NIH HHS/ -- P01 GM047467/GM/NIGMS NIH HHS/ -- P01 GM047467-20/GM/NIGMS NIH HHS/ -- P01CA089021/CA/NCI NIH HHS/ -- P01GM047467/GM/NIGMS NIH HHS/ -- P30 CA006516/CA/NCI NIH HHS/ -- P30 CA006516-43S1/CA/NCI NIH HHS/ -- R01 AI078063/AI/NIAID NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- R01-GM56302/GM/NIGMS NIH HHS/ -- R21 CA128620/CA/NCI NIH HHS/ -- R21/R33 DK070299/DK/NIDDK NIH HHS/ -- R33 DK070299/DK/NIDDK NIH HHS/ -- R33 DK070299-03/DK/NIDDK NIH HHS/ -- T32 CA009172/CA/NCI NIH HHS/ -- T32 CA009361/CA/NCI NIH HHS/ -- T32 CA009361-28/CA/NCI NIH HHS/ -- New York, N.Y. -- Science. 2010 Sep 17;329(5998):1492-9. doi: 10.1126/science.1188015.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20847263" target="_blank"〉PubMed〈/a〉
    Keywords: Adenosine Triphosphate/metabolism ; Animals ; Cell Line ; Cell Line, Tumor ; *Cell Proliferation ; Female ; Glucose/*metabolism ; Glyceric Acids/metabolism ; *Glycolysis ; Histidine/metabolism ; Humans ; Isoenzymes/metabolism ; Kinetics ; Male ; Mammary Neoplasms, Animal/metabolism ; Mice ; Neoplasms/*metabolism/pathology ; Phosphoenolpyruvate/metabolism ; Phosphoglycerate Mutase/*metabolism ; Phosphopyruvate Hydratase/metabolism ; Phosphorylation ; Prostatic Neoplasms/metabolism ; Pyruvate Kinase/*metabolism ; Pyruvic Acid/metabolism ; Recombinant Proteins/metabolism
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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  • 4
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    The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin (2005)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2005-11-26
    Description: The Peutz-Jegher syndrome tumor-suppressor gene encodes a protein-threonine kinase, LKB1, which phosphorylates and activates AMPK [adenosine monophosphate (AMP)-activated protein kinase]. The deletion of LKB1 in the liver of adult mice resulted in a nearly complete loss of AMPK activity. Loss of LKB1 function resulted in hyperglycemia with increased gluconeogenic and lipogenic gene expression. In LKB1-deficient livers, TORC2, a transcriptional coactivator of CREB (cAMP response element-binding protein), was dephosphorylated and entered the nucleus, driving the expression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which in turn drives gluconeogenesis. Adenoviral small hairpin RNA (shRNA) for TORC2 reduced PGC-1alpha expression and normalized blood glucose levels in mice with deleted liver LKB1, indicating that TORC2 is a critical target of LKB1/AMPK signals in the regulation of gluconeogenesis. Finally, we show that metformin, one of the most widely prescribed type 2 diabetes therapeutics, requires LKB1 in the liver to lower blood glucose levels.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074427/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3074427/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shaw, Reuben J -- Lamia, Katja A -- Vasquez, Debbie -- Koo, Seung-Hoi -- Bardeesy, Nabeel -- Depinho, Ronald A -- Montminy, Marc -- Cantley, Lewis C -- CA84313/CA/NCI NIH HHS/ -- GM056203/GM/NIGMS NIH HHS/ -- GM37828/GM/NIGMS NIH HHS/ -- R01 GM056203/GM/NIGMS NIH HHS/ -- R01 GM056203-09/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2005 Dec 9;310(5754):1642-6. Epub 2005 Nov 24.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA. shaw@salk.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16308421" target="_blank"〉PubMed〈/a〉
    Keywords: AMP-Activated Protein Kinases ; Animals ; Blood Glucose/analysis ; Diabetes Mellitus, Type 2/drug therapy/metabolism ; Enzyme Activation ; Female ; Gene Expression Regulation ; Gluconeogenesis/genetics ; Glucose/*metabolism ; HeLa Cells ; Homeostasis ; Humans ; Hyperglycemia/drug therapy/metabolism ; Hypoglycemic Agents/*pharmacology/therapeutic use ; Lipogenesis/genetics ; Liver/enzymology/*metabolism ; Male ; Metformin/*pharmacology/therapeutic use ; Mice ; Mice, Obese ; Multienzyme Complexes/*metabolism ; Phosphorylation ; Protein-Serine-Threonine Kinases/genetics/*metabolism ; Signal Transduction ; Trans-Activators/genetics/metabolism ; Transcription Factors
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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