A cytoplasmic PML mutant inhibits p53 function
A cytoplasmic PML mutant inhibits p53 function
复制标题
DOI：
10.4161/cc.5.22.3504
复制
发表时间：
2006-11-15
期刊：
影响因子：
4.3
通讯作者：
Salomoni, Paolo
中科院分区：
文献类型：
--
作者：
Bellodi, Cristian;Kindle, Karin;Salomoni, Paolo
早幼粒细胞白血病基因（Pml）是在急性早幼粒细胞白血病（APL）中鉴定的肿瘤抑制基因，其中由于染色体易位t（15; 17），其与RAR α基因融合。Pml编码细胞核和细胞质两种亚型。虽然核PML已被深入研究，但胞质PML蛋白的特征较少。PML核同种型（nPML）是称为PML核体（PML-NB）的亚核结构的基本组分。为了响应细胞损伤（例如DNA损伤和致癌激活），nPML通过CBP介导的乙酰化调节p53活性并激活其促凋亡和生长抑制功能。在侵袭性APL病例中发现了两种错义突变，导致PML胞浆蛋白截短（Mut PML）。在这里，我们报告，胞质PML能够诱导nPML的迁移到细胞质，从而减少PML-NB的数量。值得注意的是，Mut PML抑制p53转录、生长抑制和凋亡功能，从而表明PML的细胞质表达通过抑制核PML对存活产生影响。总的来说，我们的研究结果揭示了PML细胞质蛋白在p53调控中的作用。
The promyelocytic leukaemia gene (Pml) is a tumor suppressor identified in acute promyelocytic leukaemia (APL), where it is fused to RAR alpha gene as a result of the chromosomal translocation t( 15; 17). Pml encodes both nuclear and cytoplasmic isoforms. While nuclear PML has been intensively investigated, cytoplasmic PML proteins are less characterized. PML nuclear isoforms (nPML) are the essential components of sub-nuclear structures referred to as PML nuclear bodies (PML-NB). In response to cellular insults such as DNA damage and oncogenic activation, nPML modulates p53 activity through CBP-mediated acetylation and activates its pro-apoptotic and growth suppressive functions. Two missense mutations resulting in truncated PML cytoplasmic proteins (Mut PML) have been identified in aggressive APL cases. Here we report that cytoplasmic PML is able to induce the relocation of nPML to the cytoplasm, thus reducing the number of PML-NBs. Remarkably, Mut PML inhibits p53 transcriptional, growth suppressive, and apoptotic functions, thus suggesting that cytoplasmic expression of PML has an impact on survival through inhibition of nuclear PML. Overall our findings shed new light on the role of PML cytoplasmic proteins in the regulation of p53.