Our previous study have shown that the PSMD11 protein was an important survival factor for cancer cells except for its key role in regulation of assembly and activity of the 26S proteasome. To further investigate the role of PSMD11 in carcinogenesis, we constructed a conditional exon 5 floxed allele of PSMD11 (PSMD11flx) in mice. It was found that homozygous PSMD11 flx/flx mice showed normal and exhibited a normal life span and fertility, and showed roughly equivalent expression of PSMD11 in various tissues, suggesting that the floxed allele maintained the wild-type function. Cre recombinase could induce efficient knockout of the floxed PSMD11 allele both in vitro and in vivo. Mice with constitutive single allele deletion of PSMD11 derived from intercrossing between PSMD11flx/flx and CMV-Cre mice were all viable and fertile, and showed apparent growth retardation, suggesting that PSMD11 played a significant role in the development of mice pre- or postnatally. No whole-body PSMD11 deficient embryos (PSMD11−/−) were identified in E7.5–8.5 embryos in uteros, indicating that double allele knockout of PSMD11 leads to early embryonic lethality. To avoid embryonic lethality produced by whole-body PSMD11 deletion, we further developed conditional PSMD11 global knockout mice with genotype Flp;FSF-R26CAG − CreERT2/+; PSMD11 flx/flx, and demonstrated that PSMD11 could be depleted in a temporal and tissue-specific manner. Meanwhile, it was found that depletion of PSMD11 could induce massive apoptosis in MEFs. In summary, our data demonstrated that we have successfully generated a conditional knockout allele of PSMD11 in mice, and found that PSMD11 played a key role in early and postnatal development in mice, the PSMD11 flx/flx mice will be an invaluable tool to explore the functions of PSMD11 in development and diseases.

中文翻译：

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小鼠 PSMD11 基因条件性敲除等位基因的产生和鉴定

我们之前的研究表明，PSMD11 蛋白是癌细胞的重要生存因子，除了它在调节 26S 蛋白酶体的组装和活性方面的关键作用。为了进一步研究 PSMD11 在致癌作用中的作用，我们在小鼠中构建了 PSMD11 (PSMD11flx) 的条件外显子 5 floxed 等位基因。发现纯合PSMD11 flx/flx小鼠表现正常，并表现出正常的寿命和生育能力，并且PSMD11在各种组织中的表达大致相当，表明floxed等位基因保持了野生型功能。Cre重组酶可以在体外和体内诱导有效敲除floxed PSMD11等位基因。由 PSMD11flx/flx 和 CMV-Cre 小鼠之间的杂交衍生的 PSMD11 组成性单等位基因缺失的小鼠都是可行的和肥沃的，并表现出明显的生长迟缓，表明PSMD11在小鼠出生前或出生后的发育中发挥了重要作用。在子宫内 E7.5-8.5 胚胎中未发现全身 PSMD11 缺陷胚胎 (PSMD11-/-)，表明 PSMD11 的双等位基因敲除导致早期胚胎致死率。为了避免全身 PSMD11 缺失产生的胚胎致死率，我们进一步开发了基因型为 Flp 的条件性 PSMD11 全局敲除小鼠；FSF-R26CAG - CreERT2/+；PSMD11 flx/flx，并证明 PSMD11 可以以时间和组织特异性方式耗尽。同时，发现PSMD11的消耗可诱导MEF中的大量细胞凋亡。总之，我们的数据表明我们已经成功地在小鼠中产生了 PSMD11 的条件性敲除等位基因，