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DNA damage induces a novel p53-survivin signaling pathway regulating cell cycle and apoptosis in acute lymphoblastic leukemia cells.
- Source :
-
The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2002 Oct; Vol. 303 (1), pp. 124-31. - Publication Year :
- 2002
-
Abstract
- Survivin is a novel member of the inhibitor of apoptosis protein (IAP) family. Here we report that the chemotherapeutic drug doxorubicin, a DNA-damaging agent, activates a p53-survivin signaling pathway inducing cell cycle arrest and apoptosis in childhood acute lymphoblastic leukemia (ALL). Treatment of wild-type (wt) p53 ALL cells (EU-3 cell line) with doxorubicin caused accumulation of p53, resulting in dramatic down-regulation of survivin, depletion of cells in G(2)/M, and apoptosis (increased sub-G(1) compartment). In contrast, doxorubicin treatment of mutant (mut) p53 cells (EU-6/ALL line) up-regulated survivin and induced G(2)/M arrest without inducing apoptosis. However, treating EU-6 with anti-survivin antisense resensitized these cells to doxorubicin, resulting in apoptosis. With a p53-null cell line (EU-4), although doxorubicin treatment arrested cells in G(2)/M, survivin expression was unchanged, and cells underwent only limited apoptosis. However, re-expression of wt-p53 in EU-4 cells could restore the doxorubicin-p53-survivin pathway, resulting in significantly decreased survivin expression and increased apoptosis in these cells after doxorubicin treatment. Following cotransfection of p53-null EU-4 cells with survivin promoter-luciferase constructs and either wt-p53 or different mut-p53 expression vectors, wt-p53 inhibited survivin promoter activity; p53-mediated inhibition could be abrogated by overexpression of murine double minute2 (MDM2) protein. Together, these studies define a novel p53-survivin signaling pathway activated by DNA damage that results in down-regulation of survivin, cell cycle arrest, and apoptosis. Furthermore, our data indicate that loss of wt-p53 function in tumor cells may contribute to up-regulation of survivin and resistance to DNA-damaging agents.
- Subjects :
- Chromosomal Proteins, Non-Histone physiology
Cysteine Proteinase Inhibitors physiology
Humans
Inhibitor of Apoptosis Proteins
Luciferases genetics
Neoplasm Proteins
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Recombinant Proteins metabolism
Survivin
Transcription, Genetic
Transfection
Tumor Cells, Cultured
Tumor Suppressor Protein p53 physiology
Apoptosis physiology
Cell Cycle physiology
Chromosomal Proteins, Non-Histone genetics
DNA Damage
Microtubule-Associated Proteins
Signal Transduction physiology
Tumor Suppressor Protein p53 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 0022-3565
- Volume :
- 303
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of pharmacology and experimental therapeutics
- Publication Type :
- Academic Journal
- Accession number :
- 12235242
- Full Text :
- https://doi.org/10.1124/jpet.102.037192