Zippo Alessio, De Robertis Alessandra, Serafini Riccardo, Oliviero Salvatore
Dipartimento di Biologia Molecolare Università di Siena, Via Fiorentina 1, 53100 Siena, Italy.
Nat Cell Biol. 2007 Aug;9(8):932-44. doi: 10.1038/ncb1618. Epub 2007 Jul 22.
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.
丝氨酸/苏氨酸激酶人类Pim1（以下简称PIM1）在细胞周期进程和肿瘤发生过程中与人类c-Myc（以下简称MYC）协同作用。然而，这种协同作用的本质仍不清楚。在此我们表明，在生长因子刺激后，PIM1通过MYC BoxII（MBII）结构域与MYC和MAX（Myc相关因子X）的二聚体形成复合物。MYC将PIM1招募至MYC靶基因FOSL1（FRA-1）和ID2的E盒，PIM1使MYC结合位点处核小体上的组蛋白H3的丝氨酸10（H3S10）磷酸化，促进它们的转录激活。MYC和PIM1在活跃转录位点共定位，表达谱分析显示PIM1对20%的MYC调控基因的调节有作用。此外，PIM1依赖的H3S10磷酸化有助于MYC的转化能力。这些结果确立了PIM1作为一种MYC辅因子的新功能，该辅因子使MYC靶位点处的染色质磷酸化，并表明在E盒处的核小体磷酸化有助于MYC依赖的转录激活和细胞转化。
