Abstract
The upstream stimulatory factor 2 (USF2) is a regulator of important cellular processes and is supposed to have also a role during tumor development. However, the knowledge about the mechanisms that control the function of USF2 is limited. The data of the current study show that USF2 function is regulated by phosphorylation and identified GSK3β as an USF2-phosphorylating kinase. The phosphorylation sites within USF2 could be mapped to serine 155 and threonine 230. In silico analyses of the 3-dimensional structure revealed that phosphorylation of USF2 by GSK3β converts it to a more open conformation which may influence transactivity, DNA binding and target gene expression. Indeed, experiments with GSK-3β-deficient cells revealed that USF2 transactivity, DNA binding and target gene expression were reduced upon lack of GSK3β. Further, experiments with USF2 variants mimicking GSK3β phosphorylated USF2 in GSK3β-deficient cells showed that phosphorylation of USF2 by GSK3β did not affect cell proliferation but increased cell migration. Together, this study reports a new mechanism by which USF2 may contribute to cancerogenesis.
Highlights
The upstream stimulatory factors (USFs) are involved in the transcriptional regulation of various genes whose products contribute to the stress and immune response, to cell cycle and proliferation as well as to lipid and carbohydrate metabolism [1]
Since we found that parts of the upstream stimulatory factor 2 (USF2) protein sequence match with the substrate recognition preferences of glycogen synthase kinase 3b (GSK3b) [28] we aimed to investigate whether GSK3b can phosphorylate USF2 in intact cells and whether this affects USF2 function
We found that threonine and serine phosphorylated USF2 could be detected in the wild-type cells whereas none of these forms could be detected in GSK3b2/2 mouse embryonic fibroblasts (MEFs) (Fig. 1A)
Summary
The upstream stimulatory factors (USFs) are involved in the transcriptional regulation of various genes whose products contribute to the stress and immune response, to cell cycle and proliferation as well as to lipid and carbohydrate metabolism [1]. The usf and usf genes are ubiquitously expressed with varying ratios in different organs [2]. All USF proteins belong to the basic helix-loop-helix leucine zipper (b-HLH-LZ) transcription factor family [4]. They contain a highly conserved USF-specific region (USR) [5] and bind preferably as USF1/USF2 heterodimers [3] to E-boxes with a 59-CANNTG-39 core sequence in the promoter of their viral or cellular target genes [6]
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