| Abstract | 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. |
| Authors | Li Hui, Vanessa Rodrik, Rafal M Pielak, Stefan Knirr, Yang Zheng, David A Foster
(Affiliation: Department of Biological Sciences, Hunter College of the City University of New York, New York, New York 10021, USA.)
|
| Journal | The Journal of biological chemistry
(J Biol Chem)
Vol. 280
Issue 43
Pg. 35829-35
(Oct 28 2005)
ISSN: 0021-9258 United States |
| PMID | 16109716
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
|
| Chemical References |
- Adaptor Proteins, Signal Transducing
- Antigens, Polyomavirus Transforming
- Carrier Proteins
- EIF4EBP1 protein, human
- Phosphoproteins
- RNA, Small Interfering
- Serine
- mTOR protein
- Protein Kinases
- Ribosomal Protein S6 Kinases
- Phosphoprotein Phosphatases
- Protein Phosphatase 2
- Phospholipase D
|
| Topics |
- Adaptor Proteins, Signal Transducing
- Antigens, Polyomavirus Transforming
(metabolism)
- Apoptosis
- Blotting, Western
- Breast Neoplasms
(pathology)
- Carrier Proteins
(metabolism)
- Cell Line, Tumor
- Cell Survival
- Humans
- Immunoprecipitation
- Models, Biological
- Mutation
- Phospholipase D
(chemistry, metabolism)
- Phosphoprotein Phosphatases
(antagonists & inhibitors)
- Phosphoproteins
(metabolism)
- Phosphorylation
- Protein Kinases
(metabolism, physiology)
- Protein Phosphatase 2
- RNA, Small Interfering
(metabolism)
- Ribosomal Protein S6 Kinases
(metabolism)
- Ribosomes
(enzymology)
- Serine
(chemistry)
|
