BRG-1, a component of the human SWI/SNF complex, either activates or represses cellular promoters by modulating chromatin structure via the formation of a multiple polypeptide complex. Human papillomavirus E7 binds and destabilizes pRb, resulting in the blockage of G 1 arrest in the cell cycle. We show here that the highrisk human papillomavirus E7 protein group binds BRG-1 and modulates repression of the c-fos promoter mediated by this protein. In addition, both wild-type and Rb binding-defective E7 proteins abolish flat cell formation by BRG-1 in SW13 cells, whereas E7 COOHterminal mutants do not affect this process. BRG-1-triggered repression of the c-fos promoter is sensitive to trichostatin A. We further establish that BRG-1 contains an activation domain and a trichostatin A-sensitive repression domain. These results collectively suggest that the viral oncogene E7 targets both pRb and BRG-1 via protein-protein interactions, resulting in the deregulation of host cell cycle control.Oncogenic transformation is often caused by the aberrant expression of key genes that regulate growth properties of the cell. Many transcription factors possess DNA binding properties to modulate cellular gene expression. These DNA-binding proteins frequently communicate with other cellular co-factors, such as co-activators and co-repressors, and regulate target gene expression through modification of the chromatin structure (1).Brm-related gene 1 (BRG-1), 1 a component of the human SWI/SNF complex, is a homolog of Drosophila melanogaster brahma and Saccharomyces cerevisiae SNF2 (2). BRG-1 is crucial to the function of the SWI/SNF nucleosome remodeling complex and interacts with various cellular factors, such as BRCA1, pRb, and several transcription factors (3-8). BRG-1 also binds to cyclin E and alters the ability of this protein to induce growth arrest (9). In SW13 cells that do not express either BRG-1 or hBrm but contain wild-type pRb, overexpression of BRG-1 leads to flat cell formation (5). A recent study by de la Serna et al. (10) demonstrated that the dominant negative form of BRG-1 blocks MyoD-mediated muscle differentiation. Interestingly, a BRG-1 null mouse displays an embryonic lethal phenotype and its heterozygotes are predisposed to exencephaly and tumors, indicating that this protein plays a role in the suppression of tumor formation (11). The nuclear receptor co-repressor and mSin3A co-purify with the SWI/SNF complex, suggesting that these distinct multiprotein complexes are involved in transcriptional repression (12, 13). Although the detailed molecular mechanism of interaction between SWI/SNF and the co-repressor complex remains to be elucidated, we speculate that the two complexes act in concert to repress target genes, using histone deacetylase (HDAC) and chromatin remodeling activity.Human papillomaviruses (HPVs) of the high-risk group (e.g. HPV-16) cause cancers in humans, whereas papillomaviruses of the low-risk group (e.g. HPV-11) cause benign epithelial hyperproliferation (14). Papillomavirus E7 associates...

Folate deficiency and hyperhomocysteinemia are found in most patients with alcoholic liver disease. Oxidative stress is one of the most important mechanisms contributing to homocysteine (Hcy)-induced tissue injury. However it has not been examined whether exogenous administration of folic acid attenuates oxidative stress and hepatic toxicity. The aim of this study was to investigate the in vivo effect of folic acid supplementation on oxidative stress and hepatic toxicity induced by chronic ethanol consumption. Wistar rats (n = 32) were divided into four groups and fed 0%, 12%, 36% ethanol, or 36% ethanol plus folic acid (10 mg folic acid/L) diets. After 5 weeks, chronic consumption of the 36% ethanol diet significantly increased plasma alanine transaminase (ALT) (P < 0.05) and aspartate transaminase (AST) (P < 0.05), triglycerides (TG) (P < 0.05), Hcy (P < 0.001), and low density lipoprotein conjugated dienes (CD) (P < 0.05) but decreased total radical-trapping antioxidant potential (TRAP) (P < 0.001). These changes were prevented partially by folic acid supplementation. The 12% ethanol diet had no apparent effect on most parameters. Plasma Hcy concentration was well correlated with plasma ALT (r = 0.612**), AST (r = 0.652*), CD (r = 0.495*), and TRAP (r = -0.486*). The results indicate that moderately elevated Hcy is associated with increased oxidative stress and liver injury in alcohol-fed rats, and suggests that folic acid supplementation appears to attenuate hepatic toxicity induced by chronic ethanol consumption possibly by decreasing oxidative stress.

No abstract

We compared the preventive capacity of high intakes of vitamin C (VC) and vitamin E (VE) on oxidative stress and liver toxicity in rats fed a low-fat ethanol diet. Thirty-two Wistar rats received the low fat (10% of total calories) Lieber-DeCarli liquid diet as follows: either ethanol alone (Alc group, 36% of total calories) or ethanol in combination with VC (Alc + VC group, 40 mg VC/100 g body weight) or VE (Alc + VE group, 0.8 mg VE/100 g body weight). Control rats were pair-fed a liquid diet with the Alc group. Ethanol administration induced a modest increase in alanine aminotransferase (ALT), aspartate aminotransferase (AST), conjugated dienes (CD), and triglycerides but decreased total radical-trapping antioxidant potential (TRAP) in plasma. VE supplementation to alcohol-fed rats restored the plasma levels of AST, CD, and TRAP to control levels. However, VC supplementation did not significantly influence plasma ALT, AST, or CD. In addition, a significant increase in plasma aminothiols such as homocysteine and cysteine was observed in the Alc group, but cysteinylglycine and glutathione (GSH) did not change by ethanol feeding. Supplementing alcohol-fed rats with VC increased plasma GSH and hepatic S-adenosylmethionine, but plasma levels of aminothiols, except GSH, were not influenced by either VC or VE supplementation in ethanol-fed rats. These results indicate that a low-fat ethanol diet induces oxidative stress and consequent liver toxicity similar to a high-fat ethanol diet and that VE supplementation has a protective effect on ethanol-induced oxidative stress and liver toxicity.

We confirm that ethanol decreases hepatic 10-FTHF dehydrogenase activity and show that this decrease occurs irrespective of folate status. This shows that modulation of 10-FTHF is one possible mechanism by which ethanol intake decreases folate status and affects one-carbon metabolism.