A new role of protein phosphatase 2a in adenoviral E1A protein-mediated sensitization to anticancer drug-induced apoptosis in human breast cancer cells.

Abstract

The adenoviral type 5 E1A protein has been shown to induce sensitization to different categories of anticancer drug-induced apoptosis, partly by down-regulation of the activity of a critical oncogenic kinase Akt in both normal fibroblasts and epithelial breast cancer cells. Currently, the adenoviral E1A gene is being tested as an antitumor gene in multiple clinical trials. However, molecular mechanisms underlying E1A-mediated chemosensitization and down-regulation of Akt activity are still not completely defined. Here, we show that E1A by up-regulation of the catalytic subunit of protein phosphatase 2A [PP2A (PP2A/C)] enhanced the activity of PP2A, which results in repression of Akt activation in E1A-expressing cells. In addition, activation of PP2A/C is required for E1A-mediated sensitization to drug-induced apoptosis, because blocking PP2A/C expression using a specific small interfering RNA against PP2A/C reduced drug sensitivity in E1A-expressing cells. Deletion mutation of the conserved domain of E1A, which is required for E1A-mediated sensitization to drug-induced apoptosis, also abolished the ability of E1A to up-regulate PP2A/C. Thus, the up-regulation of PP2A may represent a novel mechanism for E1A-mediated sensitization to anticancer drug-induced apoptosis.

• Authors: Yong Liao, Mien-Chie Hung
• Journal: Cancer research (Cancer Res) Vol. 64 Issue 17 Pg. 5938-42 (Sep 01 2004) ISSN: 0008-5472 [Print] United States
• PMID: 15342371 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Adenovirus E1A Proteins
• Proto-Oncogene Proteins
• Recombinant Proteins
• Tumor Necrosis Factor-alpha
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Phosphoprotein Phosphatases
• Protein Phosphatase 2

Topics

• Adenoviridae (genetics)
• Adenovirus E1A Proteins (biosynthesis, genetics, physiology)
• Apoptosis (drug effects, physiology)
• Breast Neoplasms (drug therapy, enzymology, pathology)
• Catalytic Domain
• Cell Line, Tumor
• Enzyme Activation
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphoprotein Phosphatases (biosynthesis, metabolism, pharmacology, physiology)
• Protein Phosphatase 2
• Protein Serine-Threonine Kinases (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins (antagonists & inhibitors, metabolism)
• Proto-Oncogene Proteins c-akt
• Recombinant Proteins (pharmacology)
• Tumor Necrosis Factor-alpha (pharmacology)
• Up-Regulation
• p38 Mitogen-Activated Protein Kinases