PFKFB (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 extensively involved in cell proliferation owing to its key role in carbohydrate metabolism. In the present study we analyse its mechanism of regulation by progestins in breast cancer cells. We report that exposure of T47D cells to synthetic progestins (ORG2058 or norgestrel) leads to a rapid increase in Fru-2,6-P2 concentration. Our Western blot results are compatible with a short-term activation due to PFKFB3 isoenzyme phosphorylation and a long-term sustained action due to increased PFKFB3 protein levels. Transient transfection of T47D cells with deleted gene promoter constructs allowed us to identify a PRE (progesterone-response element) to which PR (progesterone receptor) binds and thus transactivates PFKFB3 gene transcription. PR expression in the PR-negative cell line MDA-MB-231 induces endogenous PFKFB3 expression in response to norgestrel. Direct binding of PR to the PRE box (−3490 nt) was confirmed by ChIP (chromatin immunoprecipiation) experiments. A dual mechanism affecting PFKFB3 protein and gene regulation operates in order to assure glycolysis in breast cancer cells. An immediate early response through the ERK (extracellular-signal-regulated kinase)/RSK (ribosomal S6 kinase) pathway leading to phosphorylation of PFKFB3 on Ser461 is followed by activation of mRNA transcription via cis-acting sequences on the PFKFB3 promoter.
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Research Article|
February 13 2012
Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells
Laura Novellasdemunt;
Laura Novellasdemunt
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Mercè Obach;
Mercè Obach
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Lluís Millán-Ariño;
Lluís Millán-Ariño
†Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Baldiri Reixac, 4, E-08028, Barcelona, Spain
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Anna Manzano;
Anna Manzano
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Francesc Ventura;
Francesc Ventura
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Jose Luis Rosa;
Jose Luis Rosa
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Albert Jordan;
Albert Jordan
†Institut de Biologia Molecular de Barcelona (IBMB-CSIC), Baldiri Reixac, 4, E-08028, Barcelona, Spain
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Àurea Navarro-Sabate;
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
1To whom correspondence should be addressed (email aureanavarro@ub.edu).
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Ramon Bartrons
Ramon Bartrons
2
*Departament de Ciències Fisiològiques II, IDIBELL (Institut d'Investigacró Biomèdica de Bellvitge), Campus de Bellvitge, Universitat de Barcelona, E-08907, L'Hospitalet de Llobregat, Barcelona, Spain
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Publisher: Portland Press Ltd
Received:
August 03 2011
Revision Received:
November 24 2011
Accepted:
November 24 2011
Accepted Manuscript online:
November 24 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 442 (2): 345–356.
Article history
Received:
August 03 2011
Revision Received:
November 24 2011
Accepted:
November 24 2011
Accepted Manuscript online:
November 24 2011
Citation
Laura Novellasdemunt, Mercè Obach, Lluís Millán-Ariño, Anna Manzano, Francesc Ventura, Jose Luis Rosa, Albert Jordan, Àurea Navarro-Sabate, Ramon Bartrons; Progestins activate 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) in breast cancer cells. Biochem J 1 March 2012; 442 (2): 345–356. doi: https://doi.org/10.1042/BJ20111418
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