The expression of the tumour suppressor HBP1 is down-regulated by growth factors via the PI3K/PKB/FOXO pathway.
Growth factors inactivate the FOXO (forkhead box O) transcription factors through PI3K (phosphoinositide 3-kinase) and PKB (protein kinase B). By comparing microarray data from multiple model systems, we identified HBP1 (high-mobility group-box protein 1) as a novel downstream target of this pathway. HBP1 mRNA was down-regulated by PDGF (platelet-derived growth factor), FGF (fibroblast growth factor), PI3K and PKB, whereas it was up-regulated by FOXO factors. This observation was confirmed in human and murine fibroblasts as well as in cell lines derived from leukaemia, breast adenocarcinoma and colon carcinoma. Bioinformatics analysis led to the identification of a conserved consensus FOXO-binding site in the HBP1 promoter. By luciferase activity assay and ChIP, we demonstrated that FOXO bound to this site and regulated the HBP1 promoter activity in a PI3K-dependent manner. Silencing of HBP1 by shRNA increased the proliferation of human fibroblasts in response to growth factors, suggesting that HBP1 limits cell growth. Finally, by analysing a transcriptomics dataset from The Cancer Genome Atlas, we observed that HBP1 expression was lower in breast tumours that had lost FOXO expression. In conclusion, HBP1 is a novel target of the PI3K/FOXO pathway and controls cell proliferation in response to growth factors.
*De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Alexandra
A
Coomans de Brachène
*De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Emeline
E
Bollaert
†Department of Molecular Cancer Research, University Medical Centre, 3584 CG Utrecht, The Netherlands.
Astrid
A
Eijkelenboom
*De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Audrey
A
de Rocca Serra
‡Department of Immunology, University Medical Centre, 3584 EA Utrecht, The Netherlands.
Kristan E
KE
van der Vos
†Department of Molecular Cancer Research, University Medical Centre, 3584 CG Utrecht, The Netherlands.
Boudewijn M T
BM
Burgering
‡Department of Immunology, University Medical Centre, 3584 EA Utrecht, The Netherlands.
Paul J
PJ
Coffer
*De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Ahmed
A
Essaghir
*De Duve Institute, Université Catholique de Louvain, 1200 Brussels, Belgium.
Jean-Baptiste
JB
Demoulin
D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D017124:Conserved Sequence; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000235:genetics*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006609:High Mobility Group Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D058539:Phosphatidylinositol 3-Kinase / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000235:genetics*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C486328:HBP1 protein, human; D006609:High Mobility Group Proteins; D036341:Intercellular Signaling Peptides and Proteins; D012097:Repressor Proteins; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt