Recently, data from several groups have raised the concept of 'checkpoint' in transcription. As capping of nascent RNA transcript is tightly coupled to RNA polymerase II transcription, we seek to obtain direct evidence that transcripiton checkpoint via capping enzyme functions in this early regulatory step. One of temperature sensitive (ts) alleles of ceg1, a guanylyltransferase subunit of the Saccharomyces cerevisiaecapping enzyme, showed 6-azauracil (6AU) sensitivity at the permissive growth temperature, which is a phenotype that is correlated with a transcription elongational defect. This ts allele, ceg1-63 also has an impaired ability to induce PUR5 in response to a 6AU treatment. However, this cellular and molecular defect is not due to the preferential degradation of the transcript attributed from a lack of guanylyltransferase activity. On the contrary, the data suggests that the guanylyltransferase subunit of the capping enzyme plays a role in transcription elongation. First, in addition to the 6AU sensitivity, ceg1-63is synthetically lethal with elongation defective mutations of the largest subunit of RNA polymerase II. Secondly, it exhibited a lower GAL1 mRNA turn-over after glucoseshut off. Third, it decreased the transcription read through a tandem array of promoter proximal pause sites in an orientation dependent manner. Interestingly, this mutant also showed lower pass through a pause site located further downstream of the promoter. Taken together, these results suggest that the capping enzyme plays the role of an early transcription checkpoint possibly in the step of the reversion of repression by stimulating polymerase to escape from the promoter proximal arrest once RNA becomes appropriately capped.

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting $1\%$ of the population above the age of 65 and is characterized by a selective loss of dopaminergic neurons in the substantia nigra pars compacta. Although the underlying cause of dopaminergic cell death or the mechanism by which these cells degenerate is still not clearly understood, oxidative stress, mitochondrial dysfunction, and protein misfolding are thought to play important roles in the dopaminergic degeneration in PD. Tetrahydrobiopterin (BH4) is synthesized exclusively in the monoaminergic, including dopaminergic, cells and serves as an endogenous and obligatory cofactor for syntheses of the potential oxidative stressors dopamine and nitric oxide. In addition to its contribution toward the syntheses of these two potentially toxic molecules, BH4 itself can directly generate oxidative stress. BH4 undergoes oxidation during the hydroxylation reaction as well as nonenzymatic autooxidation to produce hydrogen peroxide and superoxide radical. We have previously suggested BH4 as an endogenous molecule responsible for the dopaminergic neurodegeneration. BH4 exerts selective toxicity to dopamine-producing cells via generation of oxidative stress, mitochondrial dysfunction, and apoptosis. BH4 also induces morphological, biochemical, and behavioral characteristics associated with PD in vivo. BH4 as well as enzyme activity and gene expression of GTP cyclohydrolase I, the rate-limiting enzyme in BH4 synthesis pathway, are readily upregulated by cellular changes such as calcium influx and by various stimuli including stress situations. This points to the possibility that cellular availability of BH4 might be increased in aberrant conditions, leading to increased extracellular BH4 subsequent degeneration. The fact that BH4 is specifically and endogenously synthesized in dopaminergic cells, Is readily upregulated, and generates oxidative stress-related cell death provides physical relevance of this molecule as an attractive candidate with which to explain the mechanism of pathogenesis of PD.

This study is peformed to investigate the effect of water extract from Vaccinium uliginosum L., on melanin production in B 16 melanoma cells, procollagen production and matrix metalloproteinase-1(MMP-1) inhibition in human fibroblast cells. One hundred grams of the Vaccinium uliginosum L. was extracted with 2000 mL of water($90^{\circ}C$, 16h, 2times). The water extracts were lyophilized and stored at $4^{\circ}C$ until used. Dry weight yields of extracts of Vaccinium uliginosum L. were $3\%$(w/w). Extracts from Vaccinium uliginosum L. showed scavenger activities on DPPH radical, superoxide anion radical, hydroxyl radical, hydrogen peroxide and singlet oxygen radical. And these substances inhibited release of cyiokines from human keratinocyte after UV B exposure. Therefore we confirmed that extracts from Vaccinium uliginosum L. had antioxidative effect. These substances inhibited purified tyrosinase activity and melanogenesis in B 16 melanoma cells treated/untreated IL-$1{\alpha}$. Moreover this extract stimulated procollagen production and inhibited MMP-1 production in human fibroblast cells treated/untreated IL-$1{\beta}$. Therefore we confirmed that extracts from Vaccinium uliginosum L. had whitening effect. And these substances decreased degree of wrinkle in hairless mouse skin that induced by UV B irradiation. Therefore we confirmed that extracts from Vaccinium uliginosum L. had anti-wrinkle effect. From the above results, it is possible that Vaccinium uliginosum L. may be developed to be an anti-melanogenesis agent and anti-wrinkle agent.