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Identification of a tumour suppressor network opposing nuclear Akt function

Abstract

The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor1. In such tumours, AKT becomes enriched at cell membranes where it is activated by phosphorylation. Yet many targets inhibited by phosphorylated AKT (for example, the FOXO transcription factors) are nuclear; it has remained unclear how relevant nuclear phosphorylated AKT (pAKT) function is for tumorigenesis. Here we show that the PMLtumour suppressor prevents cancer by inactivating pAKT inside the nucleus. We find in a mouse model that Pml loss markedly accelerates tumour onset, incidence and progression in Pten-heterozygous mutants, and leads to female sterility with features that recapitulate the phenotype of Foxo3a knockout mice2. We show that Pml deficiency on its own leads to tumorigenesis in the prostate, a tissue that is exquisitely sensitive to pAkt levels, and demonstrate that Pml specifically recruits the Akt phosphatase PP2a as well as pAkt into Pml nuclear bodies. Notably, we find that Pml-null cells are impaired in PP2a phosphatase activity towards Akt, and thus accumulate nuclear pAkt. As a consequence, the progressive reduction in Pml dose leads to inactivation of Foxo3a-mediated transcription of proapoptotic Bim and the cell cycle inhibitor p27kip1. Our results demonstrate that Pml orchestrates a nuclear tumour suppressor network for inactivation of nuclear pAkt, and thus highlight the importance of AKT compartmentalization in human cancer pathogenesis and treatment.

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Figure 1: Pml status dictates carcinogenesis in Pten +/- mice.
Figure 2: Pml loss leads to an increase in pAkt in vivo.
Figure 3: Pml deficiency leads to increased nuclear pAkt localization and function in vitro and in vivo.
Figure 4: Pml affects PP2a activity towards pAkt.

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Acknowledgements

We thank R. Bernardi, B. Carver, Z. Chen, S. Clohessy, T. Maeda and T. Yung for discussion, help with reagents and data analysis; W. Golden and M. S. Jiao for help with pathology analysis; and C. Le, M. Lupu and C. Matei for help with MR imaging. This work was supported by NIH grants to P.P.P. and P.P.S. as well as grants to J.A.K. and the Memorial Sloan-Kettering Cancer Center. Author Contributions The experiments were conceived and designed by L.C.T., A.A., P.P.S., J.A.K., C.C.-C. and P.P.P. Experiments were performed by L.C.T., A.A., P.P.S. and J.A.K. Data were analysed by L.C.T., A.A., P.P.S., J.A.K., C.C.-C. and P.P.P. The paper was written by L.C.T. and P.P.P.

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Correspondence to Pier Paolo Pandolfi.

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Trotman, L., Alimonti, A., Scaglioni, P. et al. Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523–527 (2006). https://doi.org/10.1038/nature04809

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