Mouse mammary tumor virus gene expression is suppressed by oligomeric ellagitannins, novel inhibitors of poly(ADP-ribose) glycohydrolase.
Oligomeric ellagitannins (nobotanins B, E, and K) were found to be potent inhibitors of poly(ADP-ribose) glycohydrolase purified from mouse mammary tumor 34I cells. Kinetic analysis revealed that the inhibition of nobotanin B (dimer) was competitive with respect to the substrate poly(ADP-ribose), whereas nobotanin E (trimer) and nobotanin K (tetramer) exhibited mixed-type inhibition. These results suggest that the dimeric structure of ellagitannin may have a functional domain that competes with poly(ADP-ribose) on the poly(ADP-ribose) glycohydrolase molecule. To determine the inhibitory effects of oligomeric ellagitannins on poly(ADP-ribose) glycohydrolase in vivo, we examined their effects on de-poly(ADP-ribosyl)ation of some chromosomal proteins in intact 34I cells that was induced by glucocorticoid treatment. Nobotanin B caused concentration-dependent inhibition of glucocorticoid-induced de-poly(ADP-ribosyl)ation of HMG 14 and 17 and histone H1 in intact 34I cells. Interestingly, this inhibition was associated with suppression of the glucocorticoid-sensitive mouse mammary tumor virus (MMTV) mRNA synthesis. In contrast, nobotanin E and K had little inhibitory effect on either de-poly(ADP-ribosyl)ation of these proteins or induction of MMTV transcription after glucocorticoid treatment. Nobotanin B but not E and K was taken into 34I cells. These results may suggest that the suppression of glucocorticoid-sensitive MMTV transcription results from in vivo inhibition of poly(ADP-ribose) glycohydrolase by nobotanin B. These results also indicate the importance of de-poly(ADP-ribosyl)ation of HMG 14 and 17 and histone H1 in regulation of transcription of the glucocorticoid-sensitive MMTV gene.
Tsai
Y J
YJ
Department of Pharmacology, Faculty of Medical Sciences, Taipei Medical College, Taiwan, Republic of China.
Aoki
T
T
Maruta
H
H
Abe
H
H
Sakagami
H
H
Hatano
T
T
Okuda
T
T
Tanuma
S
S
D000818:Animals; D001667:Binding, Competitive; D002467:Cell Nucleus / Q000201:enzymology; D015870:Gene Expression / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005814:Genes, Viral / Q000187:drug effects; D006026:Glycoside Hydrolases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D047348:Hydrolyzable Tannins; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental; D008324:Mammary Tumor Virus, Mouse / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008809:Mice, Inbred C3H; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013634:Tannins / Q000494:pharmacology*; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D047348:Hydrolyzable Tannins; D013634:Tannins; C075603:nobotanin B; C075604:nobotanin E; C075605:nobotanin K; D006026:Glycoside Hydrolases; C022407:poly ADP-ribose glycohydrolase