| Nicotinamide- and caspase-mediated inhibition of poly(ADP-ribose) polymerase are associated with p53-independent cell cycle (G2) arrest and apoptosis. | |
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MedLine Citation:
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PMID: 12619896 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Poly(ADP-ribose) polymerase (PARP), which is activated by DNA strand breaks, is involved in DNA repair and replication but, during apoptosis, undergoes early caspase-mediated cleavage. Activation of programmed cell death in response to DNA damage may rely on functional p53 protein. Tumor cells are commonly deficient in this oncogene product resulting in resistance to many cytostatic drugs. Here we report that nicotinamide-induced inhibition of poly(ADP-ribosyl)ation and cytokine-induced nitric oxide production both result in a transient increase in p53 levels in pancreatic tumor RINm5F cells. These treatments also induce disruption of the mitochondrial membrane potential (delta psi(m)), as revealed using the mitochondrial probe JC-1, followed by PARP cleavage and apoptosis all of which are inhibited by the anti-apoptotic protein Bcl-2. Moreover, PARP-inhibition by nicotinamide or 3-aminobenzamide induces apoptosis and/or cell cycle arrest at the G2 checkpoint in all of four tested tumor cell lines of both mesenchymal and epithelial origin including mouse NIH-3T3 cells and p53 deficient human HeLa and Jurkat cells. Bcl-2 counteracts cytokine-, but not nicotinamide-induced G2 arrest. These findings indicate that both chemical and caspase-mediated inhibition of PARP activity, possibly by interfering with DNA replication and repair, may promote a p53-independent G2 arrest and apoptosis. |
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Authors:
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Johan Saldeen; Linda Tillmar; Ella Karlsson; Nils Welsh |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: Molecular and cellular biochemistry Volume: 243 ISSN: 0300-8177 ISO Abbreviation: Mol. Cell. Biochem. Publication Date: 2003 Jan |
Date Detail:
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Created Date: 2003-03-06 Completed Date: 2003-11-18 Revised Date: 2006-11-15 |
Medline Journal Info:
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Nlm Unique ID: 0364456 Medline TA: Mol Cell Biochem Country: Netherlands |
Other Details:
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Languages: eng Pagination: 113-22 Citation Subset: IM |
Affiliation:
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Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden. johan.saldeen@medcellbiol.uu.se |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Benzamides / pharmacology Caspases / pharmacology* Cell Cycle Cell Nucleus / metabolism Cytokines / metabolism DNA Fragmentation Dose-Response Relationship, Drug G2 Phase Hela Cells Humans Immunoblotting Jurkat Cells Membrane Potentials Mice Microscopy, Fluorescence Models, Biological NIH 3T3 Cells Niacinamide / pharmacology* Nitric Oxide / metabolism Poly(ADP-ribose) Polymerases / antagonists & inhibitors* Proto-Oncogene Proteins c-bcl-2 / metabolism Radiation-Sensitizing Agents / pharmacology Time Factors Tumor Suppressor Protein p53 / metabolism* Ultraviolet Rays |
| Chemical | |
Reg. No./Substance:
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0/Benzamides; 0/Cytokines; 0/Proto-Oncogene Proteins c-bcl-2; 0/Radiation-Sensitizing Agents; 0/Tumor Suppressor Protein p53; 10102-43-9/Nitric Oxide; 3544-24-9/3-aminobenzamide; 98-92-0/Niacinamide; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 3.4.22.-/Caspases |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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