Identification of a tumour suppressor network opposing nuclear Akt function

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)523-527
Number of pages5
JournalNature
Volume441
Issue number7092
DOIs
StatePublished - May 25 2006

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Neoplasms
Phosphoric Monoester Hydrolases
Carcinogenesis
Female Infertility
Null Lymphocytes
Proto-Oncogenes
Knockout Mice
Prostate
Cell Cycle
Transcription Factors
Phosphorylation
Cell Membrane
Phenotype
Incidence

ASJC Scopus subject areas

  • General

Cite this

Trotman, L. C., Alimonti, A., Scaglioni, P. P., Koutcher, J. A., Cordon-Cardo, C., & Pandolfi, P. P. (2006). Identification of a tumour suppressor network opposing nuclear Akt function. Nature, 441(7092), 523-527. https://doi.org/10.1038/nature04809

Identification of a tumour suppressor network opposing nuclear Akt function. / Trotman, Lloyd C.; Alimonti, Andrea; Scaglioni, Pier Paolo; Koutcher, Jason A.; Cordon-Cardo, Carlos; Pandolfi, Pier Paolo.

In: Nature, Vol. 441, No. 7092, 25.05.2006, p. 523-527.

Research output: Contribution to journalArticle

Trotman, LC, Alimonti, A, Scaglioni, PP, Koutcher, JA, Cordon-Cardo, C & Pandolfi, PP 2006, 'Identification of a tumour suppressor network opposing nuclear Akt function', Nature, vol. 441, no. 7092, pp. 523-527. https://doi.org/10.1038/nature04809
Trotman LC, Alimonti A, Scaglioni PP, Koutcher JA, Cordon-Cardo C, Pandolfi PP. Identification of a tumour suppressor network opposing nuclear Akt function. Nature. 2006 May 25;441(7092):523-527. https://doi.org/10.1038/nature04809
Trotman, Lloyd C. ; Alimonti, Andrea ; Scaglioni, Pier Paolo ; Koutcher, Jason A. ; Cordon-Cardo, Carlos ; Pandolfi, Pier Paolo. / Identification of a tumour suppressor network opposing nuclear Akt function. In: Nature. 2006 ; Vol. 441, No. 7092. pp. 523-527.
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