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The mitogen-activated protein kinase pathway mediates growth arrest or E1A-dependent apoptosis in SKBR3 human breast cancer cells.
- Source :
-
International journal of cancer [Int J Cancer] 1998 Nov 09; Vol. 78 (4), pp. 511-7. - Publication Year :
- 1998
-
Abstract
- Previously, we have shown that phorbol ester (PMA) induces p21(WAF1/CIP1)-dependent growth arrest in SKBr3 breast cancer and LNCaP prostate cancer cells. Here, I demonstrate that inhibition of Raf-1 kinase by dominant-negative Raf-1 or pharmacological depletion of Raf-1 prevented PMA-mediated induction of p21(WAF1/CIP1). Similarly, PD98059, a specific inhibitor of MEK, abolished p21(WAF1/CIP1) induction and PMA-induced growth arrest. Like PMA, the H-ras oncogene, another activator of the Raf-1/MEK/MAPK pathway, transactivated p21(WAF1/CIP1) in SKBr3 cells. I further investigated PMA-induced growth arrest following infection of SKBr3 cells with 12S E1A-expressing adenovirus. Although high levels of E1A oncoprotein prevented both PMA-induced p21(WAF1/CIP1) and growth arrest, smaller amounts of E1A abrogated growth arrest without down-regulation of p21(WAF1/CIP1). Therefore, E1A can stimulate proliferation downstream of p21(WAF1/CIP1). Albeit less effective than full activity, either Rb- or p300-binding activity of E1A was sufficient for the abrogation of PMA-mediated growth arrest. E1A-driven proliferation of PMA-treated SKBr3 cells was accompanied by apoptosis. New therapeutic approaches can be envisioned that would utilize stimulation of the Raf-1/MEK/MAPK pathway to inhibit growth of PMA-sensitive cancer cells.
- Subjects :
- Breast Neoplasms enzymology
Cell Cycle drug effects
Cyclin-Dependent Kinase Inhibitor p21
Cyclins biosynthesis
Enzyme Activation
Humans
Isoenzymes metabolism
Protein Kinase C metabolism
Protein Kinase C-alpha
Proto-Oncogene Proteins c-raf antagonists & inhibitors
Tumor Cells, Cultured
ras Proteins metabolism
Adenovirus E1A Proteins pharmacology
Apoptosis
Breast Neoplasms pathology
Carcinogens pharmacology
Cell Division drug effects
Phorbol Esters pharmacology
Proto-Oncogene Proteins c-raf metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0020-7136
- Volume :
- 78
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 9797142
- Full Text :
- https://doi.org/10.1002/(sici)1097-0215(19981109)78:4<511::aid-ijc19>3.0.co;2-8