Document Detail


Induction of transcriptionally active Jun proteins regulates drug-induced senescence.
MedLine Citation:
PMID:  16966326     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The drug hydroxyurea (HU) is used for cancer therapy and treatment of sickle cell anemia. It inhibits cell cycle progression by blocking DNA synthesis and drives cells to undergo apoptosis or enter senescence. We demonstrate here that HU induces the expression of two AP-1 proteins, c-Jun and JunB, which exert antagonistic effects on the cell cycle. Moreover, the induction of c-Jun is observed following treatment with two other drugs that inhibit the cell cycle in S phase, aphidicolin and camptothecin. The induction of c-Jun, which promotes cell cycle progression, up-regulates expression of cyclin D after exposure of cells to HU. Deficiency in c-jun prevents elevation of cyclin D expression and extends entrance into HU-induced senescence but also renders cells more resistant to HU-dependent apoptosis. The induction of c-Jun is independent of JNK activity, and additionally, of c-Jun autoregulatory activity but is inhibited upon inhibition of protein kinase C activity. Therefore, we suggest that c-Jun activity prevents drug-induced senescence. Conversely, the JunB target gene, tumor suppressor p16(INK4a), a cyclin-dependent kinase inhibitor essential for the induction of drug-induced senescence, is also up-regulated by HU in a JunB-dependent manner. Constitutive expression of JunB up-regulates p16(INK4a) and increases the sensitivity of mouse fibroblasts to drug-induced-senescence. Thus, we suggest that in contrast to c-Jun, JunB drives cells to enter HU-dependent senescence. The effect of HU treatment, which regulates the intricate web of AP-1 transcription, depends on the balance between c-Jun and JunB activities.
Authors:
Orli Yogev; Shira Anzi; Kazushi Inoue; Eitan Shaulian
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-09-11
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  281     ISSN:  0021-9258     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2006 Nov 
Date Detail:
Created Date:  2006-11-06     Completed Date:  2006-12-21     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  34475-83     Citation Subset:  IM    
Affiliation:
Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Hadassah Ein Kerem, Jerusalem 91120, Israel.
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MeSH Terms
Descriptor/Qualifier:
Aging / drug effects*,  physiology
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Blotting, Western
Cell Cycle / drug effects
Cells, Cultured
Cyclin D1 / genetics,  metabolism
Cyclin-Dependent Kinase Inhibitor p16 / genetics,  metabolism
Fibroblasts / cytology,  drug effects,  metabolism
Gene Expression Regulation / drug effects
Humans
Hydroxyurea / pharmacology*
Kidney / cytology,  drug effects,  metabolism
Mice
Polymerase Chain Reaction
Proto-Oncogene Proteins c-fos / genetics*,  metabolism
Proto-Oncogene Proteins c-jun / genetics*,  metabolism
Transcription Factor AP-1 / genetics*,  metabolism
Transcription, Genetic / drug effects
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Proto-Oncogene Proteins c-fos; 0/Proto-Oncogene Proteins c-jun; 0/Transcription Factor AP-1; 127-07-1/Hydroxyurea; 136601-57-5/Cyclin D1

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