PIM1-dependent phosphorylation of histone H3 at serine 10 is required for MYC-dependent transcriptional activation and oncogenic transformation.
The serine/threonine kinase human Pim1 (hereafter PIM1) cooperates with human c-Myc (hereafter MYC) in cell cycle progression and tumorigenesis. However, the nature of this cooperation is still unknown. Here we show that, after stimulation with growth factor, PIM1 forms a complex with the dimer of MYC with MAX (Myc-associated factor X) via the MYC BoxII (MBII) domain. MYC recruits PIM1 to the E boxes of the MYC-target genes FOSL1 (FRA-1) and ID2, and PIM1 phosphorylates serine 10 of histone H3 (H3S10) on the nucleosome at the MYC-binding sites, contributing to their transcriptional activation. MYC and PIM1 colocalize at sites of active transcription, and expression profile analysis revealed that PIM1 contributes to the regulation of 20% of the MYC-regulated genes. Moreover, PIM1-dependent H3S10 phosphorylation contributes to MYC transforming capacity. These results establish a new function for PIM1 as a MYC cofactor that phosphorylates the chromatin at MYC-target loci and suggest that nucleosome phosphorylation, at E boxes, contributes to MYC-dependent transcriptional activation and cellular transformation.
Zippo
Alessio
A
Dipartimento di Biologia Molecolare Università di Siena, Via Fiorentina 1, 53100 Siena, Italy.
De Robertis
Alessandra
A
Serafini
Riccardo
R
Oliviero
Salvatore
S
D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000502:physiology; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D046912:Multiprotein Complexes; D009707:Nucleosomes / Q000378:metabolism; D010766:Phosphorylation; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015533:Transcriptional Activation; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099169:Fos-Related Antigen 1
D002843:Chromatin; D006657:Histones; D046912:Multiprotein Complexes; D009707:Nucleosomes; D016760:Proto-Oncogene Proteins c-fos; D016271:Proto-Oncogene Proteins c-myc; D051573:Proto-Oncogene Proteins c-pim-1; D012694:Serine; D042461:Vascular Endothelial Growth Factor A; D000099169:Fos-Related Antigen 1; C496634:PIM1 protein, human