BACKGROUND As an epigenetic regulator, the transcriptional intermediary factor 1beta (TIF1beta)/KAP1/TRIM28) has been linked to gene expression and chromatin remodeling at specific loci by association with members of the heterochromatin protein 1 (HP1) family and various other chromatin factors. The interaction between TIF1beta and HP1 is crucial for heterochromatin formation and maintenance. The HP1-box, PXVXL, of TIF1beta is responsible for its interaction with HP1. However, the underlying mechanism of how the interaction is regulated remains poorly understood. RESULTS This work demonstrates that TIF1beta is phosphorylated on Ser473, the alteration of which is dynamically associated with cell cycle progression and functionally linked to transcriptional regulation. Phosphorylation of TIF1beta/Ser473 coincides with the induction of cell cycle gene cyclin A2 at the S-phase. Interestingly, chromatin immunoprecipitation demonstrated that the promoter of cyclin A2 gene is occupied by TIF1beta and that such occupancy is inversely correlated with Ser473 phosphorylation. Additionally, when HP1beta was co-expressed with TIF1beta/S473A, but not TIF1beta/S473E, the colocalization of TIF1beta/S473A and HP1beta to the promoters of Cdc2 and Cdc25A was enhanced. Non-phosphorylated TIF1beta/Ser473 allowed greater TIF1beta association with the regulatory regions and the consequent repression of these genes. Consistent with possible inhibition of TIF1beta's corepressor function, the phosphorylation of the Ser473 residue, which is located near the HP1-interacting PXVXL motif, compromised the formation of TIF1beta-HP1 complex. Finally, we found that the phosphorylation of TIF1beta/Ser473 is mediated by the PKCdelta pathway and is closely linked to cell proliferation. CONCLUSION The modulation of HP1beta-TIF1beta interaction through the phosphorylation/de-phosphorylation of TIF1beta/Ser473 may constitute a molecular switch that regulates the expression of particular genes. Higher levels of phosphorylated TIF1beta/Ser473 may be associated with the expression of key regulatory genes for cell cycle progression and the proliferation of cells.

中文翻译：

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Ser473 处的磷酸化调节异染色质蛋白 1 结合和 TIF1beta/KAP1 的抑制功能。

背景作为表观遗传调节因子，转录中间因子 1beta (TIF1beta)/KAP1/TRIM28) 通过与异染色质蛋白 1 (HP1) 家族成员和各种其他染色质因子的关联，与特定位点的基因表达和染色质重塑相关联。TIF1beta 和 HP1 之间的相互作用对于异染色质的形成和维护至关重要。TIF1beta 的 HP1-box、PXVXL 负责其与 HP1 的交互。然而，如何调节相互作用的潜在机制仍然知之甚少。结果 这项工作表明 TIF1beta 在 Ser473 上被磷酸化，Ser473 的改变与细胞周期进程动态相关，并且在功能上与转录调控相关。TIF1beta/Ser473 的磷酸化与 S 期细胞周期基因细胞周期蛋白 A2 的诱导一致。有趣的是，染色质免疫沉淀表明细胞周期蛋白 A2 基因的启动子被 TIF1beta 占用，并且这种占用与 Ser473 磷酸化呈负相关。此外，当 HP1beta 与 TIF1beta/S473A，但不是 TIF1beta/S473E 共表达时，TIF1beta/S473A 和 HP1beta 到 Cdc2 和 Cdc25A 的启动子的共定位得到了增强。非磷酸化的 TIF1beta/Ser473 允许更大的 TIF1beta 协会与监管区域和这些基因的随之而来的镇压。与可能抑制 TIF1beta 的辅抑制因子功能一致，Ser473 残基的磷酸化，位于 HP1 相互作用的 PVPXL 基序附近，破坏了 TIF1beta-HP1 复合物的形成。最后，我们发现 TIF1beta/Ser473 的磷酸化是由 PKCdelta 通路介导的，并且与细胞增殖密切相关。结论通过TIF1beta/Ser473 的磷酸化/去磷酸化对HP1beta-TIF1beta 相互作用的调节可能构成调节特定基因表达的分子开关。较高水平的磷酸化 TIF1beta/Ser473 可能与细胞周期进程和细胞增殖的关键调控基因的表达有关。结论通过TIF1beta/Ser473 的磷酸化/去磷酸化对HP1beta-TIF1beta 相互作用的调节可能构成调节特定基因表达的分子开关。较高水平的磷酸化 TIF1beta/Ser473 可能与细胞周期进程和细胞增殖的关键调控基因的表达有关。结论通过TIF1beta/Ser473 的磷酸化/去磷酸化对HP1beta-TIF1beta 相互作用的调节可能构成调节特定基因表达的分子开关。较高水平的磷酸化 TIF1beta/Ser473 可能与细胞周期进程和细胞增殖的关键调控基因的表达有关。