Folate receptors (FR) which mediate physiological cellular folate uptake are inversely regulated by extracellular folate concentrations (EFC). Although FR upregulation in malignant cells has been accompanied by increased FR mRNA expression, we found that cervical carcinoma (HeLa-IUi) cells with >10-fold FR up-regulation at low-EFC (designated HeLa-IUrLF cells) expressed reduced FR mRNA. This prompted investigations to define the underlying mechanism(s) for alteration of FR metabolism under various EFC. When compared with high-EFC-adapted cells (designated HeLa-IUj-HF cells), HeLa-IUi-LF cells exhibited reduced transcription of FR genes, but this was partially offset by increased FR mRNA stability by ∼30%. Quantitation of biosynthetically-labeled ["S]FR identified that FR synthetic rates increased 6-fold, whereas FR degradation rates were essentially unchanged. Although propagation of HeLa-IUi-HF cells in low-EFC led to reduction of FR mRNA within 2 weeks, an increase in [35S]FR was not observed until 8 weeks. Furthermore, abrupt exposure of HeLa-IUi-LF cells to high-EFC (of various folates) tor 24-h led to an 80%- to 90% reduction in FR synthetic rates, thereby predicting eventual down-regulation of FR; however, this was accompanied by a 1.1- to 1.7-fold prolongation in the half-life of FR. Thus, in HeLa-IUi cells, regulation of FR expression by the EFC is primarily controlled at the translationa) level through alterations in FR synthetic rates. In addition, some parameters of FR metabolism were paradoxically opposite the dominant regulatory change, findings which may reflect underlying homeostatic signals that serve to limit the extent of FR regulation.
|Original language||English (US)|
|Journal||Journal of Investigative Medicine|
|State||Published - Jan 1 1996|
ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)