PTEN level in tumor suppression: how much is too little?
PTEN level in tumor suppression: how much is too little?
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DOI：
10.1158/0008-5472.can-10-2488
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发表时间：
2011-02-01
期刊：
影响因子：
11.2
通讯作者：
Pandolfi PP
中科院分区：
文献类型：
--
作者：
Carracedo A;Alimonti A;Pandolfi PP
PTEN（位于第十号染色体上的磷酸酶和张力蛋白同源物）在癌症中的重要性已经超过了它被发现时的所有预测和期望，并且使该基因成为人类癌症中最常见的突变和缺失的肿瘤抑制因子之一。PTEN水平在癌症中也经常被发现下调，即使没有遗传丢失或突变。PTEN受转录因子、microRNA、ceRNA（竞争性内源RNA，如PTEN假基因）和甲基化的高度调节，而PTEN蛋白的肿瘤抑制活性可以通过异常磷酸化、泛素化和乙酰化在多个水平上改变。这些调节信号通过改变PTEN的适当水平、定位和活性而在肿瘤发生中发挥关键作用。对所有这些水平的PTEN调控的鉴定反过来又提出了一个关键的必然问题：为了在生物体水平上赋予癌症易感性，PTEN水平或活性应该下降到多低？我们的实验室和其他人已经通过对小鼠Pten的遗传操作来解决这个问题。这项工作突出了Pten水平对肿瘤起始和进展的微妙降低的精致和组织特异性敏感性，对癌症预防和治疗具有重要意义。
The importance of PTEN (phosphatase and tensin homolog located on chromosome ten) in cancer has surpassed all predictions and expectations from the time it was discovered, and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found down-regulated in cancer also in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, ceRNAs (competitive endogenous RNAs, such as the PTEN pseudogene) and methylation, while the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization and activity of PTEN. The identification of all these levels of PTEN regulation raises in turn a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our lab and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels towards tumor initiation and progression with important implications for cancer prevention and therapy.