Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.
Selective repression of retinoic acid target genes by RIP140 during induced tumor cell differentiation of pluripotent human embryonal carcinoma cells.
复制标题
RIP140在诱导多能人类胚胎癌细胞的肿瘤细胞分化过程中对视黄酸靶基因的选择性抑制。
DOI：
10.1186/1476-4598-6-57
复制
发表时间：
2007-09-19
期刊：
影响因子：
37.3
通讯作者：
Spinella, Michael J
中科院分区：
文献类型：
--
作者：
Heim, Kelly C;White, Kristina A;Deng, Dexin;Tomlinson, Craig R;Moore, Jason H;Freemantle, Sarah J;Spinella, Michael J
由于耐药性和低功效，类维生素A作为抗癌剂的使用受到限制。核受体共调节的动力学尚不完全清楚。核受体的细胞和环境特异性活性可能部分归因于不同的靶基因子集招募了不同的共调节复合物。 RIP140（也称为 NRIP1）是一种配体依赖性辅阻遏物，可被视黄酸 (RA) 诱导。我们之前已经证明RIP140限制RA诱导的胚胎癌肿瘤细胞分化；睾丸生殖细胞肿瘤的多能干细胞。这意味着 RIP140 抑制 RA 介导的肿瘤细胞分化所需的关键基因。这些基因的鉴定将引起人们极大的兴趣。为了开始解决这个问题，采用微阵列技术以从头的方式阐明 RIP140 在胚胎癌 RA 靶基因调控中的整体作用。基因的亚类以不同的方式受到 RIP140 的影响。有趣的是，大约一半的 RA 依赖性基因不受 RIP140 的影响。因此，RIP140 似乎能够区分不同类别的 RA 靶基因。一般来说，RIP140依赖性基因表达与RIP140限制RA信号传导和肿瘤细胞分化的功能一致。很少有基因以支持 RIP140 在“主动抑制”中的作用的方式进行调节。我们还证明 RIP140 沉默使胚胎癌细胞对低剂量的 RA 敏感。这些数据共同表明，RIP140 对癌症干细胞模型中 RA 介导的基因表达具有深远影响。这里鉴定的 RIP140 依赖性 RA 靶基因可能在介导 RA 诱导的肿瘤细胞分化中特别重要，研究结果表明 RIP140 可能是使肿瘤细胞对基于类维生素A的分化治疗敏感的有吸引力的靶点。我们在 RIP140 介导的抑制模型的背景下讨论这些数据。
The use of retinoids as anti-cancer agents has been limited due to resistance and low efficacy. The dynamics of nuclear receptor coregulation are incompletely understood. Cell-and context-specific activities of nuclear receptors may be in part due to distinct coregulator complexes recruited to distinct subsets of target genes. RIP140 (also called NRIP1) is a ligand-dependent corepressor that is inducible with retinoic acid (RA). We had previously shown that RIP140 limits RA induced tumor cell differentiation of embryonal carcinoma; the pluriopotent stem cells of testicular germ cell tumors. This implies that RIP140 represses key genes required for RA-mediated tumor cell differentiation. Identification of these genes would be of considerable interest. To begin to address this issue, microarray technology was employed to elucidate in a de novo fashion the global role of RIP140 in RA target gene regulation of embryonal carcinoma. Subclasses of genes were affected by RIP140 in distinct manners. Interestingly, approximately half of the RA-dependent genes were unaffected by RIP140. Hence, RIP140 appears to discriminate between different classes of RA target genes. In general, RIP140-dependent gene expression was consistent with RIP140 functioning to limit RA signaling and tumor cell differentiation. Few if any genes were regulated in a manner to support a role for RIP140 in "active repression". We also demonstrated that RIP140 silencing sensitizes embryonal carcinoma cells to low doses of RA. Together the data demonstrates that RIP140 has profound effects on RA-mediated gene expression in this cancer stem cell model. The RIP140-dependent RA target genes identified here may be particularly important in mediating RA-induced tumor cell differentiation and the findings suggest that RIP140 may be an attractive target to sensitize tumor cells to retinoid-based differentiation therapy. We discuss these data in the context of proposed models of RIP140-mediated repression.