Regulation of Gene Expression in Endometrial Cancer Cells: Role of Extracellular Matrix in Mitochondrial Gene Expression

Summary

The biological role of mitochondria becomes increasingly important in the understanding of the regulation of physiological and pathophysiological conditions. Nevertheless, comparatively little is known about the possible factors regulating mitochondrial activity and, in particular, mitochondrial gene expression. Recently, we analyzed the molecular basis of the interaction between endometrial adenocarcinoma and reconstituted basement membrane. Applying a differential display reverse transcription-polymerase chain reaction, we identified several gene fragments with apparently differential expression patterns of corresponding mRNA. Here we report on the identification and characterization of a fragment representing the mitochondrial encoded protein NADH-dehydrogenase 6 (ND6), a protein of the electron transport chain. Northern blot hybridization confirmed the downregulation of ND6 in endometrial adenocarcinoma cells in response to a reconstituted basement membrane. We further confirmed that contact with basement membrane components represses the gene transcription of both independently controlled overlapping transcription units of the mitochondrial genome. Treatment of cells with cydoheximide did not block the mitochondrial transcription rate. Nevertheless, nuclear extracts were capable of shifting the promoter elements of mitochondrial low and heavy strand promoters, providing evidence in favor of a nuclear/mitochondrial signaling pathway. Furthermore, our study clearly shows that extracellular factors are involved in the regulation of intracellular signaling, as well as signal transfer between cellular organelles. The understanding of the molecular basis of this mechanism, its regulation, and its metabolic consequences may provide an important insight into the involvement of mitochondrial activity in the process of carcinogenesis.