Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression
Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression
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DOI：
10.1101/gad.1314405
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发表时间：
2005-08-01
影响因子：
10.5
通讯作者：
Pandolfi, PP
中科院分区：
文献类型：
--
作者：
Ma, L;Teruya-Feldstein, J;Pandolfi, PP
肿瘤抑制因子单倍体功能不全在肿瘤发生中的作用尚不清楚。PTEN和TSC2肿瘤抑制因子可拮抗Akt激活的mTOR（哺乳动物雷帕霉素靶蛋白）；因此，小鼠Pten和Tsc2的复合杂合失活原则上可能以互惠的方式加剧在单突变体中观察到的肿瘤表型。相反，我们发现虽然Tsc2杂合性揭示了Pten在生长和肿瘤抑制中的单倍性不足，但令人惊讶的是，Tsc2（+/-）突变体的肿瘤发生并没有被Pten杂合性加速，尽管Pten/Tsc2杂合性可以协同增强mTOR的激活。我们发现Pten（+/-）和Pten(+/-)Tsc2（+/-）小鼠的前列腺肿瘤中都保留了Pten和Tsc2的野生型等位基因，而Tsc2相关的肿瘤病变总是与Tsc2（+/-）和Pten(+/-)Tsc2（+/-）小鼠的Tsc2杂合性缺失（LOH）相关。这些发现表明，TSC2的失活在控制肿瘤的发生和进展方面是上位性的，重要的是，PTEN和TSC2在抑制由PTEN杂合性引发的肿瘤发生方面都是单倍不足的，而PTEN和TSC2在抑制由TSC2杂合性引起的癌变方面都是单倍不足的。为与PTEN或TSC2杂合突变相关的两种人类疾病的不同癌症易感性提供了基本原理。
The role of tumor suppressor haploinsufficiency in oncogenesis is still poorly understood. The PTEN and TSC2 tumor suppressors function to antagonize mTOR (mammalian target of rapamycin) activation by Akt; hence, compound heterozygous inactivation of Pten and Tsc2 in the mouse may in principle exacerbate the tumor phenotypes observed in the single mutants in a reciprocal manner. In contrast, we found that while Tsc2 heterozygosity unmasks Pten haploinsufficiency in growth and tumor suppression, tumorigenesis in Tsc2(+/-) mutants is surprisingly not accelerated by Pten heterozygosity, even though mTOR activation is cooperatively enhanced by compound Pten/Tsc2 heterozygosity. We show that the wild-type alleles of both Pten and Tsc2 are retained in prostate tumors from both Pten(+/-) and Pten(+/-)Tsc2(+/-) mice, whereas TSC-related tumor lesions are invariably associated with Tsc2 loss of heterozygosity (LOH) in both Tsc2(+/-) and Pten(+/-)Tsc2(+/-) mice. These findings demonstrate that inactivation of TSC2 is epistatic to PTEN in the control of tumor initiation and progression and, importantly, that both Pten and Tsc2 are haploinsufficient for suppression of tumorigenesis initiated by Pten heterozygosity, while neither Pten nor Tsc2 is haploinsufficient for repression of carcinogenesis arising from Tsc2 heterozygosity, providing a rationale for the differential cancer susceptibility of the two human conditions associated with PTEN or TSC2 heterozygous mutations.