title: PTEN down regulates AP-1 and targets c-fos in human glioma cells via PI3-kinase/Akt pathway.
abstract: The continual activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase and its mediator Akt was constitutively activated in glioma and that this might be due to the aberrant expression of their natural antagonist PTEN. The PTEN (phosphatase and tensin homologue deleted on chromosome ten) tumor suppressor gene modulates cell growth and survival through mechanisms that are incompletely understood. In this study, we investigated the possibility that PTEN mediates its effects through modulation of transcription factor AP-1, which is in part due to decrease in c-fos expression which was dependent on PI3kinase activity. Consistent with a reduction in the c-fos levels, an AP-1 dependent reporter gene was poorly induced in the PTEN expressing cell lines. In contrast to its effect on c-fos, PTEN did not affect the expression of c-Jun and other fos family members. We also show that the effect of PTEN on c-fos expression was due to its ability to antagonize PI3-kinase and could be mimicked by the expression of dominant negative Akt mutant. Taken together, these data indicate that the aberrant expression of PTEN contributes to the activation of the PI3kinase/Akt pathway and its transcription factor mediators in glioma. We conclude that the ectopic expression of PTEN down regulates the proliferation of glioma cells through the suppression of AP-1 and that this target might be essential for its central role in the growth and survival of glioma cancer cells.
authors.affiliation: Department of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. Dkoul@mdanderson.org
authors.forename: Dimpy
authors.initials: D
authors.lastname: Koul
authors.forename: Ruijun
authors.initials: R
authors.lastname: Shen
authors.forename: Shishir
authors.initials: S
authors.lastname: Shishodia
authors.forename: Yasanuri
authors.initials: Y
authors.lastname: Takada
authors.forename: Krishna P
authors.initials: KP
authors.lastname: Bhat
authors.forename: Shrikanth A G
authors.initials: SA
authors.lastname: Reddy
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017930:Genes, Reporter; D005910:Glioma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human