FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation.
FBXW7 influences murine intestinal homeostasis and cancer, targeting Notch, Jun, and DEK for degradation.
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DOI：
10.1084/jem.20100830
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发表时间：
2011-02-14
期刊：
影响因子：
--
通讯作者：
Nateri AS
中科院分区：
文献类型：
--
作者：
Babaei-Jadidi R;Li N;Saadeddin A;Spencer-Dene B;Jandke A;Muhammad B;Ibrahim EE;Muraleedharan R;Abuzinadah M;Davis H;Lewis A;Watson S;Behrens A;Tomlinson I;Nateri AS
E3泛素连接酶组分FBXW 7调节小鼠肠中的稳态并抑制肿瘤发生。SCF（Skp 1/Cullin/F-box蛋白）E3泛素连接酶复合物的Fbxw 7（F-box/WD重复序列蛋白7;也称为CDC 4、Sel 10、Ago和Fbw 7）组分在几种组织中作为肿瘤抑制因子，靶向多种转录激活因子和原癌基因进行泛素介导的降解。为了了解Fbxw 7在小鼠肠道中的功能，在本研究中，我们使用Villin-Cre（Fbxw 7 ΔG）特异性地删除了小鼠肠道中的Fbxw 7。在野生型小鼠中，肠道中Fbxw 7的缺失改变了肠上皮的稳态，导致Notch和c-Jun表达升高，并诱导9-10月龄时腺瘤的发展。在APC（腺瘤性结肠息肉病）缺陷（ApcMin/+小鼠）的情况下，Fbxw 7的缺失加速了肠肿瘤发生和死亡，并促进了腺瘤中β-连环蛋白在晚期而非早期时间点的积累。在早期时间点，Fbxw 7突变肿瘤显示DEK原癌基因的积累。DEK表达促进细胞分裂和改变原肌球蛋白（TPM）RNA的剪接，这也可能影响细胞增殖。在FBXW 7突变体人结直肠肿瘤组织中也检测到DEK积累和改变的TPM RNA剪接。鉴于其寿命缩短和肠道肿瘤发生率增加，ApcMin/+ Fbxw 7 ΔG小鼠可用于致癌性试验和药物筛选。
The E3 ubiquitin ligase component FBXW7 modulates homeostasis and inhibits tumorigenesis in the murine intestine. The Fbxw7 (F-box/WD repeat–containing protein 7; also called CDC4, Sel10, Ago, and Fbw7) component of the SCF (Skp1/Cullin/F-box protein) E3 ubiquitin ligase complex acts as a tumor suppressor in several tissues and targets multiple transcriptional activators and protooncogenes for ubiquitin-mediated degradation. To understand Fbxw7 function in the murine intestine, in this study, we specifically deleted Fbxw7 in the murine gut using Villin-Cre (Fbxw7ΔG). In wild-type mice, loss of Fbxw7 in the gut altered homeostasis of the intestinal epithelium, resulted in elevated Notch and c-Jun expression, and induced development of adenomas at 9–10 mo of age. In the context of APC (adenomatous polyposis coli) deficiency (ApcMin/+ mice), loss of Fbxw7 accelerated intestinal tumorigenesis and death and promoted accumulation of β-catenin in adenomas at late but not early time points. At early time points, Fbxw7 mutant tumors showed accumulation of the DEK protooncogene. DEK expression promoted cell division and altered splicing of tropomyosin (TPM) RNA, which may also influence cell proliferation. DEK accumulation and altered TPM RNA splicing were also detected in FBXW7 mutant human colorectal tumor tissues. Given their reduced lifespan and increased incidence of intestinal tumors, ApcMin/+Fbxw7ΔG mice may be used for testing carcinogenicity and drug screening.
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