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EMBO Mol Med. 2011 May;3(5):249-57. doi: 10.1002/emmm.201100130. Epub 2011 Mar 8.

Pml represses tumour progression through inhibition of mTOR.

Author information

  • 1Cancer 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. bernardi.rosa@hsr.it

Abstract

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.

PMID:
21387562
PMCID:
PMC3123467
DOI:
10.1002/emmm.201100130
[PubMed - indexed for MEDLINE]
Free PMC Article
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