Starvation actively inhibits splicing of glucose-6-phosphate dehydrogenase mRNA via a bifunctional ESE/ESS element bound by hnRNP K.

Regulated expression of glucose-6-phosphate dehydrogenase (G6PD) is due to changes in the rate of pre-mRNA splicing and not changes in its transcription. Starvation alters pre-mRNA splicing by decreasing the rate of intron removal, leading to intron retention and a decrease in the accumulation of mature mRNA. A regulatory element within exon 12 of G6PD pre-mRNA controls splicing efficiency. Starvation caused an increase in the expression of heterogeneous nuclear ribonucleoprotein (hnRNP) K protein and this increase coincided with the increase in the binding of hnRNP K to the regulatory element and a decrease in the expression of G6PD mRNA. HnRNP K bound to two C-rich motifs forming an ESS within exon 12. Overexpression of hnRNP K decreased the splicing and expression of G6PD mRNA, while siRNA-mediated depletion of hnRNP K caused an increase in the splicing and expression of G6PD mRNA. Binding of hnRNP K to the regulatory element was enhanced in vivo by starvation coinciding with a decrease in G6PD mRNA. HnRNP K binding to the C-rich motifs blocked binding of serine-arginine rich, splicing factor 3 (SRSF3), a splicing enhancer. Thus hnRNP K is a nutrient regulated splicing factor responsible for the inhibition of the splicing of G6PD during starvation.

[Potential carcinogenic factors in cervical intraepithelial neoplasia]. / Studie potenciálních karcinogenních faktoru u cervikálních intraepitelových neoplazií.

In a group of 22 women with cervical intraepithelial neoplasia and carcinoma of the cervix uteri and in a control group of 37 healthy women, a number of anamnestic and objective data about factors influencing these women and about consequences of such influence were analysed. Statistically significant differences between patients and controls were found in the character of work performed (physical vs. intellectual, p = 0.0312), the presence of stressing factors at the workplace (p = 0.02), a higher number of consumed meals per day in the control group (p = 0.0009), daily consumption of beer in a higher percentage of patients (p = 0.0015), the frequency of sexual intercourse in the last 2-3 months before the diagnosis of disease or examination (higher in controls, p = 0.0164) and subjective rating of sexual life in the fourth decade (better rating in controls, p = 0.0005). No differences were found between patients and controls in the number of sexual partners, the presence of antibodies against HSV-2 and other factors. According to data presented and data in the literature, external environment, some of the characteristics of sexual life and particularly infection with certain types of papillomaviruses have a certain influence on the development of cervical neoplasias.

Prospective study on the relationship between cervical neoplasia and herpes simplex type-2 virus. I. Epidemiological characteristics.

To determine the risk associated with previous herpes simplex type-2 (HSV-2) infection and possibly other virus infections, a prospective study of cervical neoplasia in more than 10,000 women was performed in the 1975-1983 period. The subjects were selected at random from an alphabetical listing of eligible women living in one district of Prague. At enrollment colposcopy and cervical cytology were performed, a blood sample was taken and data regarding education, socio-economic status, personal habits and sexual and reproduction-associated attributes were obtained from each woman. A total of 10,683 women were enrolled; a complete set of data was obtained in 10,389 women. Women with normal or non-significant findings were invited for further colposcopical and cytological investigations after 2 years and 4 years, the other women were followed at 3- to 6-monthly intervals. In women with highly significant findings, histological investigation was performed. The total of 150 cases of moderate to severe dysplasia (i.e. cervical intraepithelial neoplasia, grade II, CIN II), 83 cases of carcinoma in situ (CIN III) and 21 cases of invasive carcinoma (INCA) were detected. More than 60% of the patients were ill at enrollment, the other cases developed in subjects with originally slightly suspicious (27 CIN II, 17 CIN III, 3 INCA) or negative findings (30 CIN II, 12 CIN III, 3 INCA). Analysis of the data indicated significantly positive correlation of one or more of these clinical conditions with a number of sexual and reproduction-related attributes of which early age at first intercourse was most consistent. Among the other attributes, the smoking habit was associated with the highest risk of developing the disease. A negative correlation of cervical neoplasia with several attributes was demonstrated; of these diathermoelectrocoagulation of the ectopic epithelium and transformation zone of cervix was the most important single protective factor. On the basis of these findings, control subjects were selected for serological studies.