Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Division of Genetics, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
EMBO Mol Med. 2011 May;3(5):249-57. doi: 10.1002/emmm.201100130. Epub 2011 Mar 8.
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.
早幼粒细胞白血病基因 PML 是一种多效性肿瘤抑制因子。我们最近证明，PML 可在缺氧条件下拮抗 mTOR-HIF1α-VEGF 信号通路。为了确定 PML-mTOR 拮抗作用在肿瘤发生中的相关性，我们将 Pml 基因敲除小鼠与 Tsc2 杂合子小鼠进行了杂交，这些小鼠会发展出肾囊肿和癌，表现出 mTOR 的上调。我们发现，Pml 和 Tsc2 的联合失活会导致肿瘤前肾脏和肾脏病变中异常的 TORC1 活性。这种增加与肿瘤进展的显著加速相关，影响了肾细胞癌的生物学和组织学。此外，Pml 的失活会降低 wt Tsc2 等位基因杂合性丢失 (LOH) 的速率。有趣的是，然而，异常的 TORC1 活性不会加速 Tsc2/Pml 突变体中的肾囊肿形成。我们的数据表明，mTOR 的激活对于肿瘤的进展是至关重要的，但对于肾脏中的肿瘤起始则不是必需的。
