Pml represses tumour progression through inhibition of mTOR

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.

[1]  A. F. Castro,et al.  Rheb activates AMPK and reduces p27Kip1 levels in Tsc2-null cells via mTORC1-independent mechanisms: implications for cell proliferation and tumorigenesis , 2010, Oncogene.

[2]  J. Brugarolas,et al.  Loss of Tsc1, but not Pten, in renal tubular cells causes polycystic kidney disease by activating mTORC1. , 2009, Human molecular genetics.

[3]  Chin-Lee Wu,et al.  Signaling events downstream of mammalian target of rapamycin complex 2 are attenuated in cells and tumors deficient for the tuberous sclerosis complex tumor suppressors. , 2009, Cancer research.

[4]  R. Sandford,et al.  Defects in cell polarity underlie TSC and ADPKD-associated cystogenesis. , 2009, Human molecular genetics.

[5]  H. Lane,et al.  Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis , 2009, Molecular Cancer.

[6]  J. Sampson.  Therapeutic targeting of mTOR in tuberous sclerosis. , 2009, Biochemical Society transactions.

[7]  B. Manning,et al.  A complex interplay between Akt, TSC2 and the two mTOR complexes. , 2009, Biochemical Society transactions.

[8]  L. Harris,et al.  Capecitabine is associated with lower chemotherapy-related expenditures than those associated with gemcitabine in women with metastatic breast cancer. , 2009 .

[9]  T. Kobayashi,et al.  The G1556S-type tuberin variant suppresses tumor formation in tuberous sclerosis 2 mutant (Eker) rats despite its deficiency in mTOR inhibition , 2008, Oncogene.

[10]  N. Hay,et al.  The two TORCs and Akt. , 2007, Developmental cell.

[11]  Rosa Bernardi,et al.  PML inhibits HIF-1α translation and neoangiogenesis through repression of mTOR , 2006, Nature.

[12]  J. Maynard,et al.  Tsc1 haploinsufficiency without mammalian target of rapamycin activation is sufficient for renal cyst formation in Tsc1+/- mice. , 2006, Cancer research.

[13]  Jason A. Koutcher,et al.  Identification of a tumour suppressor network opposing nuclear Akt function , 2006, Nature.

[14]  Rosa Bernardi,et al.  PML inhibits HIF-1alpha translation and neoangiogenesis through repression of mTOR. , 2006, Nature.

[15]  Lewis C Cantley,et al.  Feedback inhibition of Akt signaling limits the growth of tumors lacking Tsc2. , 2005, Genes & development.

[16]  P. Pandolfi,et al.  Genetic analysis of Pten and Tsc2 functional interactions in the mouse reveals asymmetrical haploinsufficiency in tumor suppression. , 2005, Genes & development.

[17]  D. Griffiths,et al.  A mouse model of tuberous sclerosis 1 showing background specific early post-natal mortality and metastatic renal cell carcinoma. , 2005, Human molecular genetics.

[18]  L. S. Harrington,et al.  Restraining PI3K: mTOR signalling goes back to the membrane. , 2005, Trends in biochemical sciences.

[19]  R. Yeung,et al.  Effects of Rapamycin in the Eker Rat Model of Tuberous Sclerosis Complex , 2005, Pediatric Research.

[20]  H. Moch,et al.  Sarcomatoid Differentiation in Renal Cell Carcinoma: A Study of 101 Cases , 2001, The American journal of surgical pathology.

[21]  H. Onda,et al.  Tsc2(+/-) mice develop tumors in multiple sites that express gelsolin and are influenced by genetic background. , 1999, The Journal of clinical investigation.

[22]  T. Noda,et al.  Renal carcinogenesis, hepatic hemangiomatosis, and embryonic lethality caused by a germ-line Tsc2 mutation in mice. , 1999, Cancer research.

[23]  B. Scheithauer,et al.  Allelic loss is frequent in tuberous sclerosis kidney lesions but rare in brain lesions. , 1996, American journal of human genetics.

[24]  A. Green,et al.  The tuberous sclerosis gene on chromosome 9q34 acts as a growth suppressor. , 1994, Human molecular genetics.