Pml represses tumour progression through inhibition of mTOR.
Pml represses tumour progression through inhibition of mTOR.
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DOI：
10.1002/emmm.201100130
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发表时间：
2011-05
影响因子：
11.1
通讯作者：
Pandolfi, Pier Paolo
中科院分区：
文献类型：
--
作者：
Bernardi, Rosa;Papa, Antonella;Egia, Ainara;Coltella, Nadia;Teruya-Feldstein, Julie;Signoretti, Sabina;Pandolfi, Pier Paolo
早幼粒细胞白血病基因PML是一种多效性肿瘤抑制基因。我们最近证明PML在缺氧时对抗mTOR-HIF 1 α-VEGF信号传导。为了确定PML-mTOR拮抗作用在肿瘤发生中的相关性，我们将Pml缺失小鼠与Tsc 2杂合小鼠杂交，这些小鼠出现了mTOR上调的肾囊肿和癌。我们发现Pml和Tsc 2的组合失活导致肿瘤前肾脏和肾脏病变中的异常TORC 1活性。这种增加与肿瘤进展的显著加速相关，影响肾癌的生物学和组织学。此外，Pml失活降低了野生型Tsc 2等位基因的杂合性丢失（洛）率。然而，有趣的是，异常的TORC 1活性不会加速Tsc 2/Pml突变体中的肾囊肿形成。我们的数据表明，mTOR的激活对肿瘤进展至关重要，但对肾脏中的肿瘤起始无关紧要。
The promyelocytic leukaemia gene PML is a pleiotropic tumour suppressor. We have recently demonstrated that PML opposes mTOR-HIF1α-VEGF signalling in hypoxia. To determine the relevance of PML-mTOR antagonism in tumourigenesis, we have intercrossed Pml null mice with Tsc2 heterozygous mice, which develop kidney cysts and carcinomas exhibiting mTOR upregulation. We find that combined inactivation of Pml and Tsc2 results in aberrant TORC1 activity both in pre-tumoural kidneys as well as in kidney lesions. Such increase correlates with a marked acceleration in tumour progression, impacting on both the biology and histology of kidney carcinomas. Also, Pml inactivation decreases the rate of loss of heterozygosity (LOH) for the wt Tsc2 allele. Interestingly, however, aberrant TORC1 activity does not accelerate renal cystogenesis in Tsc2/Pml mutants. Our data demonstrate that activation of mTOR is critical for tumour progression, but not for tumour initiation in the kidney.
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