ASPL-TFE3 Oncoprotein Regulates Cell Cycle Progression and Induces Cellular Senescence by Up-Regulating p21.
ASPL-TFE3 Oncoprotein Regulates Cell Cycle Progression and Induces Cellular Senescence by Up-Regulating p21.
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DOI：
10.1016/j.neo.2016.08.001
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发表时间：
2016-10
期刊：
影响因子：
4.8
通讯作者：
Yoshida, Haruhiko
中科院分区：
文献类型：
--
作者：
Ishiguro, Naoko;Yoshida, Haruhiko
腺泡状软组织肉瘤是一种极其罕见的软组织肉瘤，预后较差。其特征是不平衡的经常性染色体易位der(17)t(X;17)(p11;q25)，导致ASPL-TFE3融合基因的产生。 ASPL-TFE3 癌蛋白作为异常转录因子发挥作用，被认为在肺泡软组织肉瘤的肿瘤发生中发挥关键作用。然而，人们对潜在的分子机制知之甚少。在本研究中，我们确定 p21 (p21WAF1/CIP1) 是 ASPL-TFE3 的直接转录靶标。 293 细胞中的异位 ASPL-TFE3 表达导致细胞周期停滞以及 p21 蛋白和 mRNA 水平显着增加。 ASPL-TFE3 通过与 p21 启动子区域的直接转录相互作用，以不依赖于 p53 的方式激活 p21 表达。当 ASPL-TFE3 以四环素诱导的方式在人骨髓来源的间充质干细胞中表达时，我们观察到 p21 表达上调和衰老相关 β-半乳糖苷酶活性的诱导。 p21 的抑制显着降低了 ASPL-TFE3 介导的细胞衰老的诱导。此外，间充质干细胞中 ASPL-TFE3 的表达导致与衰老相关分泌表型（SASP）相关的促炎细胞因子显着上调。这些结果表明 ASPL-TFE3 通过上调 p21 表达来调节细胞周期进程并诱导细胞衰老。此外，我们的数据表明，ASPL-TFE3 诱导的衰老可能通过诱导 SASP 在肿瘤发生中发挥作用，从而促进促肿瘤微环境。
Alveolar soft part sarcoma is an extremely rare soft tissue sarcoma with poor prognosis. It is characterized by the unbalanced recurrent chromosomal translocation der(17)t(X;17)(p11;q25), resulting in the generation of an ASPL-TFE3 fusion gene. ASPL-TFE3 oncoprotein functions as an aberrant transcriptional factor and is considered to play a crucial role in the tumorigenesis of alveolar soft part sarcoma. However, the underlying molecular mechanisms are poorly understood. In this study, we identified p21 (p21WAF1/CIP1) as a direct transcriptional target of ASPL-TFE3. Ectopic ASPL-TFE3 expression in 293 cells resulted in cell cycle arrest and significant increases in protein and mRNA levels of p21. ASPL-TFE3 activated p21 expression in a p53-independent manner through direct transcriptional interactions with the p21 promoter region. When ASPL-TFE3 was expressed in human bone marrow–derived mesenchymal stem cells in a tetracycline-inducible manner, we observed the up-regulation of p21 expression and the induction of senescence-associated β-galactosidase activity. Suppression of p21 significantly decreased the induction of ASPL-TFE3-mediated cellular senescence. Furthermore, ASPL-TFE3 expression in mesenchymal stem cells resulted in a significant up-regulation of proinflammatory cytokines associated with senescence-associated secretory phenotype (SASP). These results show that ASPL-TFE3 regulates cell cycle progression and induces cellular senescence by up-regulating p21 expression. In addition, our data suggest a potential mechanism by which ASPL-TFE3-induced senescence may play a role in tumorigenesis by inducing SASP, which could promote the protumorigenic microenvironment.
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影响因子：
78.5
作者：
Collado, Manuel;Serrano, Manuel
通讯作者：
Serrano, Manuel
DOI：
10.1146/annurev-pathol-121808-102144
发表时间：
2010
期刊：
Annual review of pathology
影响因子：
--
作者：
Coppé JP;Desprez PY;Krtolica A;Campisi J
通讯作者：
Campisi J
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
64.5
作者：
ELDEIRY, WS;TOKINO, T;VOGELSTEIN, B
通讯作者：
VOGELSTEIN, B
影响因子：
3.7
作者：
Huang, Weihua;Goldfischer, Michael;Zhong, Minghao
通讯作者：
Zhong, Minghao