{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T11:36:43Z","timestamp":1791113803077,"version":"4.1.0"},"reference-count":42,"publisher":"Portland Press Ltd.","issue":"3","content-domain":{"domain":["portlandpress.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,6,15]]},"abstract":"<jats:p>PFK-2\/FBPase-2 (6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase) catalyses the synthesis and degradation of Fru-2,6-P2 (fructose 2,6-bisphosphate), a key modulator of glycolysis and gluconeogenesis. The PFKFB3 gene is involved in cell proliferation owing to its role in carbohydrate metabolism. In the present study we analysed the mechanism of regulation of PFKFB3 as an immediate early gene controlled by stress stimuli that activates the p38\/MK2 [MAPK (mitogen-activated protein kinase)-activated protein kinase 2] pathway. We report that exposure of HeLa and T98G cells to different stress stimuli (NaCl, H2O2, UV radiation and anisomycin) leads to a rapid increase (15\u201330\u00a0min) in PFKFB3 mRNA levels. The use of specific inhibitors in combination with MK2-deficient cells implicate control by the protein kinase MK2. Transient transfection of HeLa cells with deleted gene promoter constructs allowed us to identify an SRE (serum-response element) to which SRF (serum-response factor) binds and thus transactivates PFKFB3 gene transcription. Direct binding of phospho-SRF to the SRE sequence (\u2212918\u00a0nt) was confirmed by ChIP (chromatin immunoprecipiation) assays. Moreover, PFKFB3 isoenzyme phosphorylation at Ser461 by MK2 increases PFK-2 activity. Taken together, the results of the present study suggest a multimodal mechanism of stress stimuli affecting PFKFB3 transcriptional regulation and kinase activation by protein phosphorylation, resulting in an increase in Fru-2,6-P2 concentration and stimulation of glycolysis in cancer cells.<\/jats:p>","DOI":"10.1042\/bj20121886","type":"journal-article","created":{"date-parts":[[2013,4,3]],"date-time":"2013-04-03T08:20:40Z","timestamp":1364977240000},"page":"531-543","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":77,"title":["PFKFB3 activation in cancer cells by the p38\/MK2 pathway in response to stress stimuli"],"prefix":"10.1042","volume":"452","author":[{"given":"Laura","family":"Novellasdemunt","sequence":"first","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurent","family":"Bultot","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Catholique de Louvain and de Duve Institute, Avenue Hippocrate, 75, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Manzano","sequence":"additional","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesc","family":"Ventura","sequence":"additional","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose\u00a0Luis","family":"Rosa","sequence":"additional","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Didier","family":"Vertommen","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Catholique de Louvain and de Duve Institute, Avenue Hippocrate, 75, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark\u00a0H.","family":"Rider","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Catholique de Louvain and de Duve Institute, Avenue Hippocrate, 75, Brussels B-1200, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"\u00c0urea","family":"Navarro-Sabate","sequence":"additional","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramon","family":"Bartrons","sequence":"additional","affiliation":[{"name":"Departament de Ci\u00e8ncies Fisiol\u00f2giques II, IDIBELL, Campus de Ci\u00e8ncies de la Salut, Universitat de Barcelona, L\u2019Hospitalet de Llobregat, Barcelona E-08907, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2013,5,31]]},"reference":[{"key":"2021112215520569600_B1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1126\/science.123.3191.309","article-title":"On the origin of cancer cells","volume":"123","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"2021112215520569600_B2","first-page":"315","article-title":"Fructose 2,6-bisphosphate","volume":"59","author":"Van Schaftingen","year":"1987","journal-title":"Adv. Enzymol. Relat. Areas Mol. Biol."},{"key":"2021112215520569600_B3","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1042\/BJ20040752","article-title":"6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase: head-to-head with a bifunctional enzyme that controls glycolysis","volume":"381","author":"Rider","year":"2004","journal-title":"Biochem. J."},{"key":"2021112215520569600_B4","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1073\/pnas.96.6.3047","article-title":"An inducible gene product for 6-phosphofructo-2-kinase with an AU-rich instability element: role in tumor cell glycolysis and the Warburg effect","volume":"96","author":"Chesney","year":"1999","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021112215520569600_B5","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/S0167-4889(02)00169-6","article-title":"Insulin induces PFKFB3 gene expression in HT29 human colon adenocarcinoma cells","volume":"1589","author":"Riera","year":"2002","journal-title":"Biochim. Biophys. Acta"},{"key":"2021112215520569600_B6","doi-asserted-by":"crossref","first-page":"5784","DOI":"10.1158\/1078-0432.CCR-05-0149","article-title":"Phosphorylation of the 6-phosphofructo-2-kinase\/fructose 2,6-bisphosphatase\/PFKFB3 family of glycolytic regulators in human cancer","volume":"11","author":"Bando","year":"2005","journal-title":"Clin. Cancer Res."},{"key":"2021112215520569600_B7","doi-asserted-by":"crossref","first-page":"53562","DOI":"10.1074\/jbc.M406096200","article-title":"6-Phosphofructo-2-kinase (pfkfb3) gene promoter contains hypoxia-inducible factor-1 binding sites necessary for transactivation in response to hypoxia","volume":"279","author":"Obach","year":"2004","journal-title":"J. Biol. Chem."},{"key":"2021112215520569600_B8","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.biochi.2005.04.007","article-title":"Overexpression of 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-4\u00a0in the human breast and colon malignant tumors","volume":"87","author":"Minchenko","year":"2005","journal-title":"Biochimie"},{"key":"2021112215520569600_B9","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1042\/BJ20101104","article-title":"Androgen stimulates glycolysis for de novo lipid synthesis by increasing the activities of hexokinase 2 and 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase 2\u00a0in prostate cancer cells","volume":"433","author":"Moon","year":"2011","journal-title":"Biochem. J."},{"key":"2021112215520569600_B10","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1271\/bbb.61.1949","article-title":"Human placental fructose-6-phosphate,2-kinase\/fructose-2,6-bisphosphatase: its isozymic form, expression and characterization","volume":"61","author":"Sakakibara","year":"1997","journal-title":"Biosci. Biotechnol. Biochem."},{"key":"2021112215520569600_B11","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1159\/000015181","article-title":"Molecular cloning, expression, and chromosomal localization of a ubiquitously expressed human 6-phosphofructo-2-kinase\/fructose-2, 6-bisphosphatase gene (PFKFB3)","volume":"83","author":"Manzano","year":"1998","journal-title":"Cytogenet. Cell Genet."},{"key":"2021112215520569600_B12","doi-asserted-by":"crossref","first-page":"4555","DOI":"10.1111\/j.1742-4658.2009.07161.x","article-title":"Pfkfb3 is transcriptionally upregulated in diabetic mouse liver through proliferative signals","volume":"276","author":"Duran","year":"2009","journal-title":"FEBS J."},{"key":"2021112215520569600_B13","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.yexmp.2009.01.003","article-title":"Regulation of glucose metabolism by 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatases in cancer","volume":"86","author":"Yalcin","year":"2009","journal-title":"Exp. Mol. Pathol."},{"key":"2021112215520569600_B14","doi-asserted-by":"crossref","first-page":"3308","DOI":"10.1016\/j.febslet.2006.04.093","article-title":"PFKFB3 gene silencing decreases glycolysis, induces cell-cycle delay and inhibits anchorage-independent growth in HeLa cells","volume":"580","author":"Calvo","year":"2006","journal-title":"FEBS Lett."},{"key":"2021112215520569600_B15","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s11060-007-9471-7","article-title":"6-Phosphofructo-2-kinase\/fructose-2,6-bisphosphatase (PFKFB3) is up-regulated in high-grade astrocytomas","volume":"86","author":"Kessler","year":"2008","journal-title":"J. Neuro-Oncol."},{"key":"2021112215520569600_B16","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1042\/BJ20111418","article-title":"Progestins activate 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells","volume":"442","author":"Novellasdemunt","year":"2012","journal-title":"Biochem. J."},{"key":"2021112215520569600_B17","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1272\/jnms.77.97","article-title":"Interleukin 6 enhances glycolysis through expression of the glycolytic enzymes hexokinase 2 and 6-phosphofructo-2-kinase\/fructose-2,6-bisphosphatase-3","volume":"77","author":"Ando","year":"2010","journal-title":"J. Nippon Med. Sch."},{"key":"2021112215520569600_B18","doi-asserted-by":"crossref","first-page":"19247","DOI":"10.1074\/jbc.M110.190298","article-title":"Cooperation of adenosine with macrophage Toll-4 receptor agonists leads to increased glycolytic flux through the enhanced expression of PFKFB3 gene","volume":"286","author":"Ruiz-Garcia","year":"2011","journal-title":"J. Biol. 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Cell Biol."},{"key":"2021112215520569600_B26","doi-asserted-by":"crossref","first-page":"14434","DOI":"10.1074\/jbc.274.20.14434","article-title":"MAPKAP kinase 2 phosphorylates serum response factor in\u00a0vitro and in\u00a0vivo","volume":"274","author":"Heidenreich","year":"1999","journal-title":"J. Biol. Chem."},{"key":"2021112215520569600_B27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0378-1119(03)00747-9","article-title":"Role of MADS box proteins and their cofactors in combinatorial control of gene expression and cell development","volume":"316","author":"Messenguy","year":"2003","journal-title":"Gene"},{"key":"2021112215520569600_B28","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1038\/376490a0","article-title":"Structure of serum response factor core bound to DNA","volume":"376","author":"Pellegrini","year":"1995","journal-title":"Nature"},{"key":"2021112215520569600_B29","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/S0022-2828(03)00110-X","article-title":"Serum response factor: toggling between disparate programs of gene expression","volume":"35","author":"Miano","year":"2003","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2021112215520569600_B30","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1432-1033.1982.tb07039.x","article-title":"A kinetic study of pyrophosphate: fructose-6-phosphate phosphotransferase from potato tubers. Application to a microassay of fructose 2,6-bisphosphate","volume":"129","author":"Van Schaftingen","year":"1982","journal-title":"Eur. J. Biochem."},{"key":"2021112215520569600_B31","first-page":"1464","article-title":"L(+)-lactate determination with lactate dehydrogenase and NAD","volume-title":"Methods of Enzymatic Analysis","author":"Gutmann","year":"1974"},{"key":"2021112215520569600_B32","doi-asserted-by":"crossref","first-page":"18505","DOI":"10.1074\/jbc.M802053200","article-title":"AMP-activated protein kinase phosphorylates and desensitizes smooth muscle myosin light chain kinase","volume":"283","author":"Horman","year":"2008","journal-title":"J. Biol. Chem."},{"key":"2021112215520569600_B33","doi-asserted-by":"crossref","first-page":"19567","DOI":"10.1074\/jbc.M001357200","article-title":"Regulation of protein kinase D by multisite phosphorylation. Identification of phosphorylation sites by mass spectrometry and characterization by site-directed mutagenesis","volume":"275","author":"Vertommen","year":"2000","journal-title":"J. Biol. Chem."},{"key":"2021112215520569600_B34","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/0955-0674(94)90035-3","article-title":"Signal transduction from the cell surface to the nucleus through the phosphorylation of transcription factors","volume":"6","author":"Karin","year":"1994","journal-title":"Curr. Opin. Cell Biol."},{"key":"2021112215520569600_B35","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S0955-0674(96)80067-6","article-title":"Regulation of transcription by MAP kinase cascades","volume":"8","author":"Treisman","year":"1996","journal-title":"Curr. Opin. Cell Biol."},{"key":"2021112215520569600_B36","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1128\/MMBR.68.2.320-344.2004","article-title":"ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions","volume":"68","author":"Roux","year":"2004","journal-title":"Microbiol. Mol. Biol. 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Chem."},{"key":"2021112215520569600_B40","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/S0014-5793(03)00808-1","article-title":"Regulation of ubiquitous 6-phosphofructo-2-kinase by the ubiquitin-proteasome proteolytic pathway during myogenic C2C12 cell differentiation","volume":"550","author":"Riera","year":"2003","journal-title":"FEBS Lett."},{"key":"2021112215520569600_B41","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1038\/ncb1881","article-title":"The bioenergetic and antioxidant status of neurons is controlled by continuous degradation of a key glycolytic enzyme by APC\/C-Cdh1","volume":"11","author":"Herrero-Mendez","year":"2009","journal-title":"Nat. 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