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Articles by S. H Yim
Total Records ( 2 ) for S. H Yim
  S Shi , D. Y Yoon , K. C Hodge Bell , I. G Bebenek , M. J Whitekus , R Zhang , A. J Cochran , S Huerta Yepez , S. H Yim , F. J Gonzalez , A. K Jaiswal and O. Hankinson
 

Benzo[a]pyrene (B[a]P) is a ligand for the aryl hydrocarbon receptor (Ahr). After binding ligand, Ahr dimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) protein, and the dimer upregulates the transcription of Cyp1a1, Cyp1b1 and other enzymes involved in the metabolic activation of B[a]P. Arnt null mice die in utero. Mice in which Arnt deletion occurs constitutively in the epidermis die perinatally. In the current study, mice were developed in which the Arnt gene could be deleted specifically in adult skin epidermis. This deletion had no overt pathological effect. Homozygosity for a null reduced nicotinamide adenine dinucleotide (phosphate): quinone oxidoreductase allele was introduced into the above mouse strain to render it more susceptible to tumor initiation by B[a]P. Deletion of Arnt in the epidermis of this strain completely prevented the induction of skin tumors in a tumor initiation–promotion protocol in which a single topical application of B[a]P acted as the tumor-initiating event, and tumor promotion was provided by repeated topical applications of 12-O-tetradecanoyl phorbol-13-acetate (TPA). In contrast, deletion of Arnt did not prevent the induction of skin tumors in a protocol also using TPA as the promoter but using as the initiator N-methyl-N'-nitro-N-nitrosoguanidine, whose activity is unlikely to be affected by the activity of Ahr, Arnt or their target genes. These observations demonstrate that Arnt is required for tumor initiation by B[a]P in this system.

  M. N Lee , S. N Lee , S. H Kim , B Kim , B. K Jung , J. H Seo , J. H Park , J. H Choi , S. H Yim , M. R Lee , J. G Park , J. Y Yoo , J. H Kim , S. T Lee , H. M Kim , S Ryeom , K. W Kim and G. T. Oh
  Background

Vascular endothelial growth factor A (VEGFA), a critical mediator of tumor angiogenesis, is a well-characterized target of hypoxia-inducible factor 1 (HIF-1). Murine arrest-defective protein 1A (mARD1A225) acetylates HIF-1, triggering its degradation, and thus may play a role in decreased expression of VEGFA.

Methods

We generated ApcMin/+/mARD1A225 transgenic mice and quantified growth of intestinal polyps. Human gastric MKN74 and murine melanoma B16F10 cells overexpressing mARD1A225 were injected into mice, and tumor growth and metastasis were measured. VEGFA expression and microvessel density in tumors were assessed using immunohistochemistry. To evaluate the role of mARD1A225 acetylation of Lys532 in HIF-1, we injected B16F10-mARD1A225 cell lines stably expressing mutant HIF-1/K532R into mice and measured metastasis. All statistical tests were two-sided, and P values less than .05 were considered statistically significant.

Results

ApcMin/+/mARD1A225 transgenic mice (n = 25) had statistically significantly fewer intestinal polyps than ApcMin/+ mice (n = 21) (number of intestinal polyps per mouse: ApcMin/+ mice vs ApcMin/+/mARD1A225 transgenic mice, mean = 83.4 vs 38.0 polyps, difference = 45.4 polyps, 95% confidence interval [CI] = 41.8 to 48.6; P < .001). The growth and metastases of transplanted tumors were also statistically significantly reduced in mice injected with mARD1A225-overexpressing cells than in mice injected with control cells (P < .01). Moreover, overexpression of mARD1A225 decreased VEGFA expression and microvessel density in tumor xenografts (P < .04) and ApcMin/+ intestinal polyps (P = .001). Mutation of lysine 532 of HIF-1 in B16F10-mARD1A225 cells prevented HIF-1 degradation and inhibited the antimetastatic effect of mARD1A225 (P < .001).

Conclusion

mARD1A225 may be a novel upstream target that blocks VEGFA expression and tumor-related angiogenesis.

 
 
 
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