Basic anatomy and tumor biology of the RPS6KA6 gene that encodes the p90 ribosomal S6 kinase-4.
Basic anatomy and tumor biology of the RPS6KA6 gene that encodes the p90 ribosomal S6 kinase-4.
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DOI：
10.1038/onc.2012.200
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发表时间：
2013-04-04
期刊：
影响因子：
8
通讯作者：
Liao, D. J.
中科院分区：
文献类型：
--
作者：
Sun, Y.;Cao, S.;Yang, M.;Wu, S.;Wang, Z.;Lin, X.;Song, X.;Liao, D. J.
RPS 6 KA 6基因编码p90核糖体S6激酶-4（RSK 4），其仍在很大程度上未被表征。在这项研究中，我们确定了一个新的RSK 4转录起始位点和几个选择性剪接位点的5 'RACE方法。所得到的mRNA变体包含四个可能的第一起始密码子。小鼠RSK 4外显子22的前15个核苷酸（nt）以及人和小鼠RSK 4外显子21和24的倒数第二个外显子都发生了选择性剪接，但倒数第二个外显子缺失的变异体主要出现在细胞系中，而在大多数正常组织中不存在。去甲基化剂5-氮杂胞苷抑制倒数第二个外显子的缺失，而细胞周期蛋白依赖性激酶4或6的两种吲哚咔唑衍生的抑制剂诱导人RSK 4外显子21的前39个核苷酸的缺失。在研究的所有人类癌细胞系中，90-kD野生型RSK 4是稀疏的，但令人惊讶的是，如通过七种不同的抗体检测到的，表达了等于或小于72-kD的几种同种型。在免疫印迹中，这些较小的同种型中的每一种通常表现为二联体或三联体，并且这些同种型的水平在不同的细胞系和培养条件之间变化很大。细胞周期蛋白D1抑制RSK 4的表达和血清饥饿增强抑制，而c-Myc和RSK 4抑制细胞周期蛋白D1。RSK 4对细胞生长、细胞死亡和化学反应的影响取决于表达的mRNA变体或蛋白质同种型、细胞系的特异性以及锚定依赖性或非依赖性生长条件和体内情况。此外，我们还观察到，即使是给定的cDNA也可能表达为多种蛋白质;因此，当使用cDNA时，在将cDNA的生物学结果归因于预期的蛋白质之前，需要排除这种可能性。总的来说，我们的研究结果表明，RSK 4是致癌的还是肿瘤抑制的取决于许多因素。
The RPS6KA6 gene encodes the p90 ribosomal S6 kinase-4 (RSK4) that is still largely uncharacterized. In this study we identified a new RSK4 transcription initiation site and several alternative splice sites with a 5’RACE approach. The resulting mRNA variants encompass four possible first start codons. The first 15 nucleotides (nt) of exon 22 in mouse and the penultimate exon in both human (exon 21) and mouse (exon 24) RSK4 underwent alternative splicing, although the penultimate exon deleted variant appeared mainly in cell clines, but not in most normal tissues. Demethylation agent 5-azacytidine inhibited the deletion of the penultimate exon whereas two indolocarbazole-derived inhibitors of cyclin dependent kinase 4 or 6 induced deletion of the first 39 nt from exon 21 of human RSK4. In all human cancer cell lines studied, the 90-kD wild type RSK4 was sparse but, surprisingly, several isoforms at or smaller than 72-kD were expressed as detected by seven different antibodies. On immunoblots, each of these smaller isoforms often appeared as a duplet or triplet and the levels of these isoforms varied greatly among different cell lines and culture conditions. Cyclin D1 inhibited RSK4 expression and serum starvation enhanced the inhibition, whereas c-Myc and RSK4 inhibited cyclin D1. The effects of RSK4 on cell growth, cell death and chemoresponse depended on the mRNA variant or the protein isoform expressed, on the specificity of the cell lines, as well as on the anchorage-dependent or -independent growth conditions and the in vivo situation. Moreover, we also observed that even a given cDNA might be expressed to multiple proteins; therefore, when using a cDNA, one needs to exclude this possibility before attribution of the biological results from the cDNA to the anticipated protein. Collectively, our results suggest that whether RSK4 is oncogenic or tumor suppressive depends on many factors.
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