一种依赖于视黄酸的肿瘤生长抑制转录复合体是早幼粒细胞白血病-维甲酸受体α（PML-RARα）和T18癌蛋白的作用靶点。
A RA-dependent, tumour-growth suppressive transcription complex is the target of the PML-RARalpha and T18 oncoproteins.
作者信息
Zhong S, Delva L, Rachez C, Cenciarelli C, Gandini D, Zhang H, Kalantry S, Freedman L P, Pandolfi P P
机构信息
Department of Human Genetics, Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Division, Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
出版信息
Nat Genet. 1999 Nov;23(3):287-95. doi: 10.1038/15463.
PML and Tif1a are fused to RARA and Braf, respectively, resulting in the production of PML-RARalpha and Tif1alpha-B-Raf (T18) oncoproteins. Here we show that PML, Tif1alpha and RXRalpha/RARalpha function together in a transcription complex that is dependent on retinoic acid (RA). We found that PML acts as a ligand-dependent coactivator of RXRalpha/RARalpha. PML interacts with Tif1alpha and CBP. In Pml-/- cells, the RA-dependent induction of genes such as RARB2 and the ability of Tif1alpha and CBP to act as transcriptional coactivators on RA are impaired. We show that both PML and Tif1alpha are growth suppressors required for the growth-inhibitory activity of RA. T18, similar to PML-RARalpha, disrupts the RA-dependent activity of this complex in a dominant-negative manner resulting in a growth advantage. Our data define a new pathway for the control of cell growth and tumorigenesis, and provide a new model for the pathogenesis of acute promyelocytic leukaemia (APL).
早幼粒细胞白血病（PML）和Tif1a分别与维甲酸受体α（RARA）和B-Raf融合，导致产生早幼粒细胞白血病-维甲酸受体α（PML-RARα）和Tif1α-B-Raf（T18）癌蛋白。在此我们表明，PML、Tif1α和视黄酸受体α/维甲酸受体α（RXRα/RARα）在一个依赖于视黄酸（RA）的转录复合物中共同发挥作用。我们发现PML作为RXRα/RARα的配体依赖性共激活因子发挥作用。PML与Tif1α和CREB结合蛋白（CBP）相互作用。在Pml基因敲除细胞中，诸如视黄酸受体β2（RARB2）等基因的RA依赖性诱导以及Tif1α和CBP作为RA转录共激活因子的能力受损。我们表明PML和Tif1α都是RA生长抑制活性所需的生长抑制因子。T18与PML-RARα类似，以显性负性方式破坏该复合物的RA依赖性活性，从而导致生长优势。我们的数据定义了一种控制细胞生长和肿瘤发生的新途径，并为急性早幼粒细胞白血病（APL）的发病机制提供了一个新模型。
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