mTOR-dependent Suppression of Protein Phosphatase 2A Is Critical for Phospholipase D Survival Signals in Human Breast Cancer Cells

  • Hui L
  • Rodrik V
  • Pielak R
 et al. 
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A critical aspect of tumor progression is the generation of survival signals that overcome default apoptotic programs. Recent studies have revealed that elevated phospholipase D activity generates survival signals in breast and perhaps other human cancers. We report here that the elevated phospholipase D activity in the human breast cancer cell line MDA-MB-231 suppresses the activity of the putative tumor suppressor protein phosphatase 2A in a mammalian target of rapamycin (mTOR)-dependent manner. Increasing the phospholipase D activity in MCF7 cells also suppressed protein phosphatase 2A activity. Elevated phospholipase D activity suppressed association of protein phosphatase 2A with both ribosomal subunit S6-kinase and eukaryotic initiation factor 4E-binding protein 1. Suppression of protein phosphatase 2A by SV40 small t-antigen has been reported to be critical for the transformation of human cells with SV40 early region genes. Consistent with a critical role for protein phosphatase 2A in phospholipase D survival signals, either SV40 small t-antigen or pharmacological suppression of protein phosphatase 2A restored survival signals lost by the suppression of either phospholipase D or mTOR. Blocking phospholipase D signals also led to reduced phosphorylation of the pro-apoptotic protein BAD at the protein phosphatase 2A dephosphorylation site at Ser-112. The ability of phospholipase D to suppress protein phosphatase 2A identifies a critical target of an emerging phospholipase D/mTOR survival pathway in the transformation of human cells

Author-supplied keywords

  • A
  • Association
  • At
  • D
  • Gene
  • New York
  • Or
  • Pathway
  • Protein
  • Pt
  • Role
  • S6 kinase
  • SV40
  • Site
  • Subunit
  • Universities
  • breast
  • phosphatase
  • phospholipase
  • phospholipase d
  • phosphorylation
  • transformation

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  • L Hui

  • V Rodrik

  • R M Pielak

  • S Knirr

  • Y Zheng

  • D A Foster

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