CG&D
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Bhatia, M.
Right arrow Articles by Meckling-Gill, K. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bhatia, M.
Right arrow Articles by Meckling-Gill, K. A.

Cell Growth & Differentiation, Vol 7, Issue 1 91-100, Copyright © 1996 by American Association of Cancer Research


ARTICLES

Overexpression of poly(ADP-ribose) polymerase promotes cell cycle arrest and inhibits neutrophilic differentiation of NB4 acute promyelocytic leukemia cells

M Bhatia, JB Kirkland and KA Meckling-Gill
Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.

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.


This article has been cited by other articles:


Home page
Pharmacol. Rev.Home page
L. Virag and C. Szabo
The Therapeutic Potential of Poly(ADP-Ribose) Polymerase Inhibitors
Pharmacol. Rev., September 1, 2002; 54(3): 375 - 429.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
M. Uchida, S. Hanai, N. Uematsu, K. Sawamoto, H. Okano, M. Miwa, and K. Uchida
Overexpression of Poly(ADP-ribose) Polymerase Disrupts Organization of Cytoskeletal F-actin and Tissue Polarity inDrosophila
J. Biol. Chem., February 22, 2002; 277(8): 6696 - 6702.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
F. R. Sallmann, M. D. Vodenicharov, Z.-Q. Wang, and G. G. Poirier
Characterization of sPARP-1: AN ALTERNATIVE PRODUCT OF PARP-1 GENE WITH POLY(ADP-RIBOSE) POLYMERASE ACTIVITY INDEPENDENT OF DNA STRAND BREAKS
J. Biol. Chem., May 19, 2000; 275(20): 15504 - 15511.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
M. N. Cervellera and A. Sala
Poly(ADP-ribose) Polymerase Is a B-MYB Coactivator
J. Biol. Chem., April 7, 2000; 275(14): 10692 - 10696.
[Abstract] [Full Text] [PDF]


Home page
J Biol ChemHome page
S. Hanai, M. Uchida, S. Kobayashi, M. Miwa, and K. Uchida
Genomic Organization of Drosophila Poly(ADP-ribose) Polymerase and Distribution of Its mRNA during Development
J. Biol. Chem., May 8, 1998; 273(19): 11881 - 11886.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cell Growth & Differentiation
Copyright © 1996 by the American Association of Cancer Research.