This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Liu, J.-L.
Right arrow Articles by Yung, W. K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Liu, J.-L.
Right arrow Articles by Yung, W. K. A.

 Previous Article  |  Next Article 

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.



This article has been cited by other articles:

  • Lobo, G. P., Waite, K. A., Planchon, S. M., Romigh, T., Nassif, N. T., Eng, C. (2009). Germline and somatic cancer-associated mutations in the ATP-binding motifs of PTEN influence its subcellular localization and tumor suppressive function. Hum Mol Genet 18: 2851-2862 [Abstract] [Full Text]  
  • Zhu, Y., Wloch, A., Wu, Q., Peters, C., Pagenstecher, A., Bertalanffy, H., Sure, U. (2009). Involvement of PTEN Promoter Methylation in Cerebral Cavernous Malformations. Stroke 40: 820-826 [Abstract] [Full Text]  
  • Ma, L., Chang, N., Guo, S., Li, Q., Zhang, Z., Wang, W., Tong, T. (2008). CSIG Inhibits PTEN Translation in Replicative Senescence. Mol. Cell. Biol. 28: 6290-6301 [Abstract] [Full Text]  
  • Lobo, G. P., Waite, K. A., Planchon, S. M., Romigh, T., Houghton, J. A., Eng, C. (2008). ATP modulates PTEN subcellular localization in multiple cancer cell lines. Hum Mol Genet 17: 2877-2885 [Abstract] [Full Text]  
  • Fouladkou, F., Landry, T., Kawabe, H., Neeb, A., Lu, C., Brose, N., Stambolic, V., Rotin, D. (2008). The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization. Proc. Natl. Acad. Sci. USA 105: 8585-8590 [Abstract] [Full Text]  
  • Chang, C.-J., Mulholland, D. J., Valamehr, B., Mosessian, S., Sellers, W. R., Wu, H. (2008). PTEN Nuclear Localization Is Regulated by Oxidative Stress and Mediates p53-Dependent Tumor Suppression. Mol. Cell. Biol. 28: 3281-3289 [Abstract] [Full Text]  
  • Emerling, B. M., Weinberg, F., Liu, J.-L., Mak, T. W., Chandel, N. S. (2008). PTEN regulates p300-dependent hypoxia-inducible factor 1 transcriptional activity through Forkhead transcription factor 3a (FOXO3a). Proc. Natl. Acad. Sci. USA 105: 2622-2627 [Abstract] [Full Text]  
  • Tamguney, T., Stokoe, D. (2007). New insights into PTEN. J. Cell Sci. 120: 4071-4079 [Abstract] [Full Text]  
  • Liu, J.-L., Mao, Z., LaFortune, T. A., Alonso, M. M., Gallick, G. E., Fueyo, J., Yung, W.K. A. (2007). Cell Cycle Dependent Nuclear Export of Phosphatase and Tensin Homologue Tumor Suppressor Is Regulated by the Phosphoinositide-3-Kinase Signaling Cascade. Cancer Res. 67: 11054-11063 [Abstract] [Full Text]  
  • Okumura, K., Mendoza, M., Bachoo, R. M., DePinho, R. A., Cavenee, W. K., Furnari, F. B. (2006). PCAF Modulates PTEN Activity. J. Biol. Chem. 281: 26562-26568 [Abstract] [Full Text]  
  • Tsuruta, H., Kishimoto, H., Sasaki, T., Horie, Y., Natsui, M., Shibata, Y., Hamada, K., Yajima, N., Kawahara, K., Sasaki, M., Tsuchiya, N., Enomoto, K., Mak, T. W., Nakano, T., Habuchi, T., Suzuki, A. (2006). Hyperplasia and Carcinomas in Pten-Deficient Mice and Reduced PTEN Protein in Human Bladder Cancer Patients.. Cancer Res. 66: 8389-8396 [Abstract] [Full Text]  
  • Chung, J.-H., Ostrowski, M. C., Romigh, T., Minaguchi, T., Waite, K. A., Eng, C. (2006). The ERK1/2 pathway modulates nuclear PTEN-mediated cell cycle arrest by cyclin D1 transcriptional regulation. Hum Mol Genet 15: 2553-2559 [Abstract] [Full Text]  
  • Gil, A., Andres-Pons, A., Fernandez, E., Valiente, M., Torres, J., Cervera, J., Pulido, R. (2006). Nuclear Localization of PTEN by a Ran-dependent Mechanism Enhances Apoptosis: Involvement of an N-Terminal Nuclear Localization Domain and Multiple Nuclear Exclusion Motifs. Mol. Biol. Cell 17: 4002-4013 [Abstract] [Full Text]  
  • Lee, S. J., Yang, E. K., Kim, S. G. (2006). Peroxisome Proliferator-Activated Receptor-{gamma} and Retinoic Acid X Receptor {alpha} Represses the TGFbeta1 Gene via PTEN-Mediated p70 Ribosomal S6 Kinase-1 Inhibition: Role for Zf9 Dephosphorylation. Mol. Pharmacol. 70: 415-425 [Abstract] [Full Text]  
  • Agrawal, S., Eng, C. (2006). Differential expression of novel naturally occurring splice variants of PTEN and their functional consequences in Cowden syndrome and sporadic breast cancer. Hum Mol Genet 15: 777-787 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»