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. 2006 May 25;441(7092):523-7.
doi: 10.1038/nature04809. Epub 2006 May 7.

Identification of a tumour suppressor network opposing nuclear Akt function

Lloyd C Trotman  1 , Andrea Alimonti, Pier Paolo Scaglioni, Jason A Koutcher, Carlos Cordon-Cardo, Pier Paolo Pandolfi
Affiliations

Identification of a tumour suppressor network opposing nuclear Akt function

Lloyd C Trotman et al. Nature. .

Abstract

The proto-oncogene AKT (also known as PKB) is activated in many human cancers, mostly owing to loss of the PTEN tumour suppressor. 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 mice. 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 p27(kip1). 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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Figures

Figure 1
Figure 1. Pml status dictates carcinogenesis in Pten+/− mice
a, Haematoxylin and eosin (H&E) analysis of colon and prostate tissue reveals invasive adenocarcinoma in Pten+/− Pml−/− mice. Arrows show invasive glands in colonic submucosa. Scale bars, 100μm. b, Kaplan–Meier plots for disease-free survival. Average polyps per mouse (top inset) and average polyp size (bottom inset) are shown. Error bars are s.d. (see also Methods).
Figure 2
Figure 2. Pml loss leads to an increase in pAkt in vivo
a, IHC staining comparing pAkt levels and localization in Pten+/− Pml+/+ and Pten+/− Pml−/− mice. b, Haematoxylin and eosin (H&E) staining of Pml−/− prostate with high-grade prostatic intraepithelial neoplasia. Scale bars (a, b), 100μm. c, Pml status affects pAkt levels in pre-neoplastic Pten+/+ tissues.
Figure 3
Figure 3. Pml deficiency leads to increased nuclear pAkt localization and function in vitro and in vivo
a, Immunofluorescence CLSM on primary littermate Pml+/+ (w) and Pml−/−(n) MEFs seeded on the same coverslips. pAkt in Pten−/− MEFs is shown for comparison. Scale bars, 10μm. b, pAkt in immunohistochemistry staining of prostate cancers from indicated mouse models. Scale bars, 50μm. c, Foxo3a activity measured by quantitative real-time PCR of prostates of the indicated genotypes. Error bars are s.d. of triplicates.
Figure 4
Figure 4. Pml affects PP2a activity towards pAkt
a, pAkt-Thr 308/Akt ratios after okadaic acid treatment of MEFs (relative to mock, see Methods). b, Ratios from a expressed relative to untreated Pml−/− cells. Note the broken ordinate axis for clarity. c, Endogenous co-immunoprecipitation of PP2a with Pml in MEFs. Asterisks indicate leftover Pml staining, not Hsp90. d, Endogenous co-immunoprecipitation of Akt with Pml at steady state (sts), starvation (sta) and serum stimulation for times indicated. e, CLSM co-localization of endogenous Pml and PP2a in MEFs. Scale bars, 5μm. f, Anti-Flag co-immunoprecipitation of PP2a-C with Flag-tagged PML/PML mutants. White bars indicate PML/mutant migration. IgG, anti-Flag IgG heavy chains. Molecular weights are in kDa. g, CLSM co-localization of pAkt and Pml. Arrowheads indicate pAkt-deficient nuclear bodies and arrows indicate pAkt accumulation outside nuclear bodies. Scale bar, 10μm.
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