The PTEN tumor suppressor is frequently targeted in tumors and patients with PTEN hamartoma tumor syndrome (PHTS) through nonsense mutations generating premature termination codons (PTC) that may cause the translation of truncated non-functional PTEN proteins. We have previously described a global analysis of the readthrough reconstitution of the protein translation and function of the human canonical PTEN isoform by aminoglycosides. Here, we report the efficient functional readthrough reconstitution of the PTEN translational isoform PTEN-L, which displays a minimal number of PTC in its specific N-terminal extension in association with disease. We illustrate the importance of the specific PTC and its nucleotide proximal sequence for optimal readthrough and show that the more frequent human PTEN PTC variants and their mouse PTEN PTC equivalents display similar patterns of readthrough efficiency. The heterogeneous readthrough response of the different PTEN PTC variants was independent of the length of the PTEN protein being reconstituted, and we found a correlation between the amount of PTEN protein being synthesized and the PTEN readthrough efficiency. Furthermore, combination of aminoglycosides and protein synthesis inducers increased the readthrough response of specific PTEN PTC. Our results provide insights with which to improve the functional reconstitution of human-disease-related PTC pathogenic variants from PTEN isoforms by increasing protein synthesis coupled to translational readthrough.
PTEN肿瘤抑制因子在肿瘤及PTEN错构瘤肿瘤综合征（PHTS）患者中常因无义突变产生提前终止密码子（PTC）而失活，导致截短型非功能性PTEN蛋白的翻译。我们先前已系统描述了氨基糖苷类药物对经典人源PTEN亚型蛋白翻译与功能通读重建的全局性分析。本研究报道了PTEN翻译亚型PTEN-L的高效功能性通读重建，该亚型在其疾病相关的特异性N端延伸区含有极少量PTC。我们阐明了特定PTC及其邻近核苷酸序列对实现最佳通读的重要性，并证明常见的人源PTEN PTC变异体及其小鼠同源PTC具有相似的通读效率模式。不同PTEN PTC变异体的异质性通读响应与重建的PTEN蛋白长度无关，且我们发现PTEN蛋白合成量与PTEN通读效率之间存在相关性。此外，氨基糖苷类药物与蛋白质合成诱导剂的联合使用可增强特定PTEN PTC的通读响应。本研究通过增强蛋白质合成与翻译通读的协同作用，为改善PTEN亚型中人类疾病相关PTC致病变异的功能性重建提供了新见解。
肿瘤(癌症)患者之家