Search

The tumor suppressor gene HIC1 encodes a BTB/POZ transcription repressor. Its promotor is frequently hypermetylated in large numbers of tumors. HIC1 also functions as a negative modulator of the Wnt signalling pathway, which fundamentally participates in regulation of stem cell renewal of the intestinal epithelium. Thanks to its structural features the intestinal epithelium represents a convenient model tissue to study stem cells and their pathology. To overcome the embryonic lethality of the complete Hic1 "knock-out" the conditional deletion of the gene in adult mouse tissue was chosen to evaluate the Hic1 biological aktivity. By the chip expression analysis of mouse embryonic fibroblasts we discovered a number of new target genes of Hic1, the most interesting of them - in respect to cancer - we considered the Toll-like receptor 2 gene. The expression of Hic1 target genes is likely to be co-regulated by p53 although the direct regulation wasn't proved. Hic1 affects the proportion of the differentiated intestinal epithelial cells types possibly via regulation of Atoh1. After conditional deletion of Hic1 in the intestinal epithelium we observed and quantitatively confirmed a significant increase of the amounts of goblet cells. We concluded that Hic1 affects differentiation pathways in intestinal...

The mammalian biological clock is based on endogenous rhythmic oscillations of the so-called clock genes which affects the timing of the external manifestations, such as rhythmic alternations of sleep and activity. This endogenous mechanism, of which the innate period slightly deviates from the solar time, can be adjusted by various external synchronizers to the exact 24 hour period. This thesis is focused on the influence of the most prominent synchronizer, the sunlight, on the molecular basis of changes in the dynamics of internal mechanism of the oscillations in the main mammalian circadian pacemaker, the suprachiasmatic nuclei of the hypothalamus. There are numerous studies which have demonstrated the effect of various cellular signaling pathways on changes of circadian rhythms. The most common methods of assessing the oscillation phase changes, however, measure changes in output rhythms that may not always reflect the changes in the molecular mechanism itself. The aim is to evaluate which components of signaling pathways have provably shown to affect the dynamics of the rhythmic expression of clock genes.