Abstract
Annexin V is a Ca2+-dependent phospholipid binding protein. Although it has been shown to inhibit protein kinase C (PKC) in cell-free systems, its role in the intact cell is unclear. A stable MCF-7 human breast cancer cell overexpression system was established to investigate the function of annexin V. In these cells, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced phosphorylation and kinase activity of ERK1/2 were suppressed. Morphological changes induced by TPA were reduced by annexin V overexpression as well as by the pan-PKC inhibitor, bisindolylmaleimide I, and by the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor, PD98059. TPA-induced MEK1/2 and Raf-1 phosphorylation were reduced in these cells. The TPA-enhanced active Ras, and its association with Raf-1, were reduced. TPA treatment of MCF-7 cells caused an increased association of Shc with Grb2. However, this increased association was prevented in the annexin V-overexpressors. p21(WAF/CIP1) is responsible for inhibition of cell cycle progression in MCF-7 cells. TPA induced the expression of p21(WAF/CIP1) to a greater extent in MCF-7 parent and control plasmid cells than in annexin V overexpressors. PD98059 inhibited this increase, suggesting that TPA upregulation of p21(WAF/CIP1) occurs via the MEK pathway, and that annexin V overexpression blunts it. This work shows that annexin V overexpression suppresses the TPA-induced Ras/ERK signaling by inhibiting at/or upstream of Shc, possibly through the inhibition of PKCs.
Original language | English (US) |
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Pages (from-to) | 2904-2912 |
Number of pages | 9 |
Journal | Oncogene |
Volume | 19 |
Issue number | 25 |
DOIs | |
State | Published - Jun 8 2000 |
Externally published | Yes |
Keywords
- Annexin V
- MAPK
- PKC
- Signal transduction
- TPA
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Cancer Research