Editors' ChoiceCancer

Working Against Nuclear Akt

Science's STKE  30 May 2006:
Vol. 2006, Issue 337, pp. tw179
DOI: 10.1126/stke.3372006tw179

Many human cancers are associated with loss of the tumor suppressor PTEN and the consequent phosphorylation and activation of the proto-oncogene Akt, with phosphorylated Akt (pAkt) accumulating at the cell membrane. Although many pAkt targets are nuclear, the role of nuclear pAkt in tumorigenesis has been unclear. Noting that prostate and colon cancer cells (cancers associated with PTEN loss) frequently lack nuclear bodies, which depend on the promyelocytic leukemia gene (Pml), Trotman et al. crossed mice heterozygous for Pten (Pten+/–) with mice lacking Pml (Pml–/–) and showed that loss of Pml exacerbated Pten-loss-dependent tumorigenesis. In Pten+/– mice, loss of Pml led to increased pAkt abundance, particularly in the nucleus, and, in cultured mouse embryonic fibroblasts, lack of Pml was associated with enhanced Akt activation and accumulation of pAkt in the nucleus in response to serum stimulation. After serum stimulation, Pml–/– cells showed decreased nuclear abundance of the transcription factor Foxo3a (a pAkt target with tumor-suppressive activity) compared with wild-type cells; however, distribution of an Akt-insensitive Foxo3A mutant was unaffected. Moreover, loss of Pml was associated with decreased expression of Foxo3a transcriptional targets. Pharmacological analysis indicated that the increase in pAkt was associated with lack of dephosphorylation by the phosphatase PP2a. Consistent with this, Pml coimmunoprecipitated with both Akt and PP2a subunits, and confocal laser scanning microscopy indicated that both PP2a subunits and pAkt colocalized with Pml in nuclear bodies. Thus, the authors conclude that Pml regulates the nuclear inactivation of Akt and that its stabilization might present one approach to the therapy of Akt-associated tumors.

L. C. Trotman, A. Alimonti, P. P. Scaglioni, J. A. Koutcher, C. Cordon-Cardo, P. P. Pandolfi, Identification of a tumour suppressor network opposing nuclear Akt function. Nature 441, 523-527 (2006). [PubMed]