PFKFB3 activation in cancer cells by the p38/MK2 pathway in response to stress stimuli

We report that exposure of HeLa and T98G cells to different stress stimuli (NaCl, H2O2, UV radiation and anisomycin) leads to a rapid increase (15-30 minutes) in PFKFB3 mRNA levels. The use of specific inhibitors in combination with MK2-deficient cells implicate control by MK2 protein kinase. Transient transfection of HeLa cells with deleted gene promoter constructs allowed us to identify a Serum Response Element (SRE) to which Serum Response Factor (SRF) binds and thus transactivates PFKFB3 gene transcription. Direct Binding of phospho-SRF to the SRE sequence (-918 nt) was confirmed by ChIP (chromatin immunoprecipiation) assays. Moreover, PFKFB3 isoenzyme phosphorylation at Ser461 by MK2 increases PFK-2 activity. Together, the results 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.

Source: BJ Signal - April 2, 2013 Category: Biochemistry Authors: L Novellasdemunt, L Bultot, A Manzano, F Ventura, J Rosa, D Vertommen, M H Rider, À Navarro-Sabate, R Bartrons Tags: BJ Metabolism Source Type: research