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 Kim, J.-S.
Right arrow Articles by Waldman, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Kim, J.-S.
Right arrow Articles by Waldman, T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, January 2007, p. 662-677, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.00537-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Activation of p53-Dependent Growth Suppression in Human Cells by Mutations in PTEN or PIK3CA{triangledown}

Jung-Sik Kim,1 Carolyn Lee,1,2 Challice L. Bonifant,1,2 Habtom Ressom,1 and Todd Waldman1*

Department of Oncology,1 Tumor Biology Training Program, Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, Washington, D.C. 200572

Received 27 March 2006/ Returned for modification 5 June 2006/ Accepted 9 October 2006

In an effort to identify genes whose expression is regulated by activated phosphatidylinositol 3-kinase (PI3K) signaling, we performed microarray analysis and subsequent quantitative reverse transcription-PCR on an isogenic set of PTEN gene-targeted human cancer cells. Numerous p53 effectors were upregulated following PTEN deletion, including p21, GDF15, PIG3, NOXA, and PLK2. Stable depletion of p53 led to reversion of the gene expression program. Western blots revealed that p53 was stabilized in HCT116 PTEN–/– cells via an Akt1-dependent and p14ARF-independent mechanism. Stable depletion of PTEN in untransformed human fibroblasts and epithelial cells also led to upregulation of p53 and senescence-like growth arrest. Simultaneous depletion of p53 rescued this phenotype, enabling PTEN-depleted cells to continue proliferating. Next, we tested whether oncogenic PIK3CA, like inactivated PTEN, could activate p53. Retroviral expression of oncogenic human PIK3CA in MCF10A cells led to activation of p53 and upregulation of p53-regulated genes. Stable depletion of p53 reversed these PIK3CA-induced expression changes and synergized with oncogenic PIK3CA in inducing anchorage-independent growth. Finally, targeted deletion of an endogenous allele of oncogenic, but not wild-type, PIK3CA in a human cancer cell line led to a reduction in p53 levels and a decrease in the expression of p53-regulated genes. These studies demonstrate that activation of PI3K signaling by mutations in PTEN or PIK3CA can lead to activation of p53-mediated growth suppression in human cells, indicating that p53 can function as a brake on phosphatidylinositol (3,4,5)-triphosphate-induced mitogenesis during human cancer pathogenesis.

* Corresponding author. Mailing address: Lombardi Comprehensive Cancer Center, Georgetown University School of Medicine, 3970 Reservoir Road, NW, NRB E304, Washington, DC 20057. Phone: (202) 687-1340. Fax: (202) 687-7505. E-mail: waldmant{at}georgetown.edu.

{triangledown} Published ahead of print on 23 October 2006.

Molecular and Cellular Biology, January 2007, p. 662-677, Vol. 27, No. 2
0270-7306/07/$08.00+0     doi:10.1128/MCB.00537-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Chen, Z., Carracedo, A., Lin, H.-K., Koutcher, J. A., Behrendt, N., Egia, A., Alimonti, A., Carver, B. S., Gerald, W., Teruya-Feldstein, J., Loda, M., Pandolfi, P. P. (2009). Differential p53-Independent Outcomes of p19Arf Loss in Oncogenesis. Sci Signal 2: ra44-ra44 [Abstract] [Full Text]  
  • Moral, M., Segrelles, C., Lara, M. F., Martinez-Cruz, A. B., Lorz, C., Santos, M., Garcia-Escudero, R., Lu, J., Kiguchi, K., Buitrago, A., Costa, C., Saiz, C., Rodriguez-Peralto, J. L., Martinez-Tello, F. J., Rodriguez-Pinilla, M., Sanchez-Cespedes, M., Garin, M., Grande, T., Bravo, A., DiGiovanni, J., Paramio, J. M. (2009). Akt Activation Synergizes with Trp53 Loss in Oral Epithelium to Produce a Novel Mouse Model for Head and Neck Squamous Cell Carcinoma. Cancer Res. 69: 1099-1108 [Abstract] [Full Text]  
  • Gabai, V. L., Yaglom, J. A., Waldman, T., Sherman, M. Y. (2009). Heat Shock Protein Hsp72 Controls Oncogene-Induced Senescence Pathways in Cancer Cells. Mol. Cell. Biol. 29: 559-569 [Abstract] [Full Text]  
  • Renner, O., Blanco-Aparicio, C., Grassow, M., Canamero, M., Leal, J. F.M., Carnero, A. (2008). Activation of Phosphatidylinositol 3-Kinase by Membrane Localization of p110{alpha} Predisposes Mammary Glands to Neoplastic Transformation. Cancer Res. 68: 9643-9653 [Abstract] [Full Text]  
  • Kim, J.-S., Bonifant, C., Bunz, F., Lane, W. S., Waldman, T. (2008). Epitope tagging of endogenous genes in diverse human cell lines. Nucleic Acids Res 36: e127-e127 [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»