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Molecular and Cellular Biology, July 2005, p. 6211-6224, Vol. 25, No. 14
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.14.6211-6224.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Nuclear PTEN-Mediated Growth Suppression Is Independent of Akt Down-Regulation

Juinn-Lin Liu,1 Xiaoyang Sheng,1 Zsuzsanna K. Hortobagyi,1 Zhenyu Mao,1 Gary E. Gallick,2 and W. K. Alfred Yung1*

Brain Tumor Center, Department of Neuro-Oncology,1 Department of Cancer Biology, U.T. M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, Texas 770302

Received 24 August 2004/ Returned for modification 15 October 2004/ Accepted 25 March 2005

The tumor suppressor gene PTEN is a phosphoinositide phosphatase that is inactivated by deletion and/or mutation in diverse human tumors. Wild-type PTEN is expressed both in the cytoplasm and nucleus in normal cells, with a preferential nuclear localization in differentiated or resting cells. To elucidate the relationship between PTEN's subcellular localization and its biologic activities, we constructed different PTEN mutants that targeted PTEN protein into different subcellular compartments. Our data show that the subcellular localization patterns of a PTEN ({Delta}PDZB) mutant versus a G129R phosphatase mutant were indistinguishable from those of wild-type PTEN. In contrast, the Myr-PTEN mutant demonstrated an enhanced association with the cell membrane. We found that nuclear PTEN alone is capable of suppressing anchorage-independent growth and facilitating G1 arrest in U251MG cells without inhibiting Akt activity. Nuclear compartment-specific PTEN-induced growth suppression is dependent on possessing a functional lipid phosphatase domain. In addition, the down-regulation of p70S6K could be mediated, at least in part, through activation of AMP-activated protein kinase in an Akt-independent fashion. Introduction of a constitutively active mutant of Akt, Akt-DD, only partially rescues nuclear PTEN-mediated growth suppression. Our collective results provide the first direct evidence that PTEN can contribute to G1 growth arrest through an Akt-independent signaling pathway.

* Corresponding author. Mailing address: Department of Neuro-Oncology, UT M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 431, Houston, TX 77030. Phone: (713) 794-1285. Fax: (713) 794-4999. E-mail: wyung{at}mdanderson.org.

Molecular and Cellular Biology, July 2005, p. 6211-6224, Vol. 25, No. 14
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.14.6211-6224.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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