ABSTRACT: Elucidation of the relationship between poly-ADP-ribosylation and carcinogenesis has markedly progressed by the recent development
of knockout or transgenic mice models of poly(ADP-ribose) polymerase (Parp)-1, Parp-2, and poly(ADP-ribose) glycohydrolase
(Parg). Parp-1 is involved in base excision repair (BER), single- and |double-strand break repair, and chromosomal stability.
These multiple functions explain why Parp-1 deficiency enhances carcinogenesis induced by alkylating agents and that in aged animals. Parp-1 is also involved in transcriptional
regulation through protein-protein interaction as a coactivator and/or poly-ADP-ribosylation reaction and is possibly involved
in epigenetic alteration during carcinogenesis and modulation of tumor phenotypes. Parp-1-dependent cell-death accompanying
NAD depletion may be another important issue in carcinogenesis because this process could lead to the selection of Parp-1 deficient cells due to their survival advantage during cancer growth. The relationship of Parp-2, Parp-3, tankyrase and Parg
with carcinogenesis is also discussed.
01/2008: pages 203-217;
ABSTRACT: Many lines of evidence suggest that poly(ADP-ribose) polymerase-1 (Parp-1) is involved in transcriptional regulation of various genes as a coactivator or a corepressor by modulating chromatin structure. However, the impact of Parp-1-deficiency on the regulation of genome-wide gene expression has not been fully studied yet.
We employed a microarray analysis covering 12,488 genes and ESTs using mouse Parp-1-deficient (Parp-1-/-) embryonic stem (ES) cell lines and the livers of Parp-1-/- mice and their wild-type (Parp-1+/+) counterparts. Here, we demonstrate that of the 9,907 genes analyzed, in Parp-1-/- ES cells, 9.6% showed altered gene expression. Of these, 6.3% and 3.3% of the genes were down- or up-regulated by 2-fold or greater, respectively, compared with Parp-1+/+ ES cells (p < 0.05). In the livers of Parp-1-/- mice, of the 12,353 genes that were analyzed, 2.0% or 1.3% were down- and up-regulated, respectively (p < 0.05). Notably, the number of down-regulated genes was higher in both ES cells and livers, than that of the up-regulated genes. The genes that showed altered expression in ES cells or in the livers are ascribed to various cellular processes, including metabolism, signal transduction, cell cycle control and transcription. We also observed expression of the genes involved in the pathway of extraembryonic tissue development is augmented in Parp-1-/- ES cells, including H19. After withdrawal of leukemia inhibitory factor, expression of H19 as well as other trophoblast marker genes were further up-regulated in Parp-1-/- ES cells compared to Parp-1+/+ ES cells.
These results suggest that Parp-1 is required to maintain transcriptional regulation of a wide variety of genes on a genome-wide scale. The gene expression profiles in Parp-1-deficient cells may be useful to delineate the functional role of Parp-1 in epigenetic regulation of the genomes involved in various biological phenomena.
BMC Genomics 02/2007; 8:41. · 4.07 Impact Factor
ABSTRACT: The impact of poly(ADP-ribose) polymerase-1 (Parp-1)-deficiency on 4-nitroquinoline 1-oxide (4NQO)-induced carcinogenesis was studied in mice with an ICR/129Sv mixed genetic background. Parp-1(+/+), Parp-1(+/-) and Parp-1(-/-) animals given 4NQO for thirty-two weeks at 0.001% in their drinking water developed papillomas and squamous cell carcinomas of the tongue, palate and esophagus, but with no statistically significant variation with the Parp-1 genotype. Thus Parp-1 deficiency does not elevate susceptibility to carcinogenesis induced by a carcinogen which gives rise to bulky DNA lesions. This study also indicated that the ICR/129Sv mixed genetic background is associated with high yield induction of esophageal tumors by 4NQO.
Cancer Letters 10/2006; 241(1):87-92. · 4.24 Impact Factor
ABSTRACT: Bone morphogenetic protein (BMP) induces bone formation in young rodents, but aging causes a reduction in the bone-forming ability of BMP. Most patients who require bone reconstruction are relatively old. Accordingly, we examined whether anabolic hormones could restore the bone inductive activity of rhBMP-2 in aged rats. rhBMP-2 in a carrier pellet was implanted subcutaneously in both 4- and 50-week-old female Wistar rats. PTH, PGE2, or 1,25(OH)2D3 was injected every day during the period of BMP implantation. The pellets were harvested, and were examined both histologically and biochemically 2 weeks after implantation. Bone-forming ability was measured by alkaline phosphatase (ALP) activity and calcium (Ca) content. Pellets in 50-week-old rats showed a significant reduction in bone formation compared to pellets in 4-week-old rats. However, daily injections of PTH into 50-week-old rats restored both ALP activity (103 +/- 4.6%) and Ca content (105 +/- 2.6%). 1,25(OH)2D3 and PGE2 also restored Ca content (103 +/- 4.5% and 98 +/- 3.8%, respectively) and stimulated ALP activity (142 +/- 2.3% and 133 +/- 3.6%). These results show that the administration of these hormones restores bone-forming ability in aged rats. A combination treatment of these hormones with rhBMP-2 might be applicable to the reconstruction of bone defects in elderly patients.
DNA and Cell Biology 09/2003; 22(9):541-6. · 2.07 Impact Factor
ABSTRACT: The purpose of this study was to evaluate the effectiveness of simultaneous cortex bone plate (CBP) graft with particulate marrow and cancellous bone (PMCB) graft for reliable closure of palatal fistulae associated with alveolar clefts.
Following standard secondary bone graft preparation of the cleft site, CBP harvested from the medial iliac crest was inserted into the palatal deficiency. This was followed by suturing the palatal mucosa. PMCB was then packed between the cortical bone and the reconstructed nasal floor.
Ten consecutive patients with palatal fistula were operated on at Tokyo Medical and Dental University Hospital from 1998 to 2000. Primary palatal repair was performed in 7 out of 10 patients at our center and in 3 out of 10 patients at other hospitals.
Ten patients (6 boys and men, 4 girls and women) with a palatal fistula associated with an alveolar cleft were studied. Ages ranged from 12 to 26 years.
All patients underwent simultaneous CBP graft with PMCB graft for closure of palatal fistula under general anesthesia.
Complete closure of palatal fistulae were obtained in 8 out of 10 cases. A very small asymptomatic fistula remained in one patient. Total necrosis of the labial flap with a residual palatal fistula occurred in one patient.
Simultaneous CBP graft with PMCB graft could be more reliable than PMCB alone for closure of a cleft associated palatal fistula.
The Cleft Palate-Craniofacial Journal 06/2002; 39(3):364-9. · 0.82 Impact Factor