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Vol. 17, Issue 9, 4002-4013, September 2006
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Centro de Investigación Príncipe Felipe, Valencia 46013, Spain
Submitted May 3, 2006;
Revised May 25, 2006;
Accepted June 20, 2006
Monitoring Editor: John Cleveland
The targeting of the tumor suppressor PTEN protein to distinct subcellular compartments is a major regulatory mechanism of PTEN function, by controlling its access to substrates and effector proteins. Here, we investigated the molecular basis and functional consequences of PTEN nuclear/cytoplasmic distribution. PTEN accumulated in the nucleus of cells treated with apoptotic stimuli. Nuclear accumulation of PTEN was enhanced by mutations targeting motifs in distinct PTEN domains, and it was dependent on an N-terminal nuclear localization domain. Coexpression of a dominant negative Ran GTPase protein blocked PTEN accumulation in the nucleus, which was also affected by coexpression of importin 
proteins. The lipid- and protein-phosphatase activity of PTEN differentially modulated PTEN nuclear accumulation. Furthermore, catalytically active nuclear PTEN enhanced cell apoptotic responses. Our findings indicate that multiple nuclear exclusion motifs and a nuclear localization domain control PTEN nuclear localization by a Ran-dependent mechanism and suggest a proapoptotic role for PTEN in the cell nucleus.
* Present address: Keratinocyte Laboratory, Cancer Research UK, 44 Lincoln’s Inn Fields, London WCA 3PX, United Kingdom.
Address correspondence to: Rafael Pulido ( rpulido{at}cipf.es)
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