Document Detail


Overexpression of poly(ADP-ribose) polymerase promotes cell cycle arrest and inhibits neutrophilic differentiation of NB4 acute promyelocytic leukemia cells.
MedLine Citation:
PMID:  8788037     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The t(15;17) translocation causes a disruption of the retinoic acid receptor alpha (RAR-alpha) and allows for the expression of the PML-RAR alpha fusion protein considered to be responsible for the differentiation block in acute promyelocytic leukemia (APL). Patients being treated with all-trans retinoic acid (ATRA) undergo remission due to the differentiation of leukemic cells to functional neutrophils but relapse due to subsequent ATRA resistance. Our group has shown recently that NB4 cells, the only in vitro model of APL, are capable of monocytic differentiation in response to 1,25-dihydroxyvitamin D3 and 12-O-tetradecanoylphorbol-13-acetate in addition to the neutrophilic differentiation response that occurs with ATRA treatment. Poly(ADP-ribose) polymerase (PARP) is a ubiquitous protein that plays a role in DNA metabolism and repair. We have shown that, unlike HL-60 cells, NB4 cells completely down-regulate PARP in the neutrophilic lineage and up-regulate PARP 90-fold in the monocytic lineage. To ascertain whether PARP is an active participant in the bipotent differentiation of APL cells, NB4 cells were transiently transfected by lipid-mediated gene transfer with the human PARP gene under the control of the human metallothionein promoter. A 4-fold overexpression of PARP, in response to 8 microM CdCl2, promoted arrest of NB4 cells in the S phase of the cell cycle. Overexpression of PARP alone had no effect on cell viability or induction of phenotypic markers in the monocytic or neutrophilic lineages. However, increased PARP expression did result in an increase in the number of cells in the subdiploid population likely to include apoptotic cells. Overexpression of PARP, alone with 12-O-tetradecanoylphorbol-13-acetate (200 nM), 1,25-dihydroxyvitamin D3 (200 nM), or a suboptimal dose of the combined agents, did not alter the expected monocytic differentiation marker profile over cells transfected with control plasmid (pSV2Neo). In contrast, PARP overexpression blocked the appearance of phenotypic markers of terminally differentiated neutrophils in 85% of the transfected population in response to 1 microM ATRA. Comparable to wild-type NB4 cells, 90% of cells transfected with pSV2Neo developed neutrophilic differentiation markers (nitroblue tetrazolium-positive and multi-lobed nuclei) in response to 1 microM ATRA. These data suggest that overexpression of PARP arrests APL cells and blocks ATRA-induced terminal neutrophilic differentiation. We propose that normal down-regulation of PARP in NB4 cells is a requirement for neutrophilic maturation.
Authors:
M Bhatia; J B Kirkland; K A Meckling-Gill
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research     Volume:  7     ISSN:  1044-9523     ISO Abbreviation:  Cell Growth Differ.     Publication Date:  1996 Jan 
Date Detail:
Created Date:  1996-10-31     Completed Date:  1996-10-31     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  9100024     Medline TA:  Cell Growth Differ     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  91-100     Citation Subset:  IM    
Affiliation:
Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.
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MeSH Terms
Descriptor/Qualifier:
Cell Cycle / drug effects,  physiology
Cell Differentiation / physiology
Cell Division / drug effects
Cholecalciferol / pharmacology
Gene Expression / physiology
Humans
Leukemia, Promyelocytic, Acute / pathology*
Neutrophils / cytology*
Plasmids / genetics
Poly(ADP-ribose) Polymerases / genetics*,  metabolism
Sensitivity and Specificity
Tetradecanoylphorbol Acetate / pharmacology
Transfection
Tretinoin / pharmacology
Tumor Cells, Cultured / enzymology,  physiology
Chemical
Reg. No./Substance:
16561-29-8/Tetradecanoylphorbol Acetate; 302-79-4/Tretinoin; 67-97-0/Cholecalciferol; EC 2.4.2.30/Poly(ADP-ribose) Polymerases

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