Dexamethasone differentially affects the levels of calcitonin and calcitonin gene-related peptide mRNAs expressed in a human medullary thyroid carcinoma cell line

The TT cells are a continuous line of human C-cells derived from a medullary thyroid carcinoma. These cells produce large quantities of calcitonin and calcitonin gene-related peptide (CGRP) by the differential splicing of a single calcitonin gene transcript. We have used specific cDNA probes for calcitonin and CGRP to study the regulation of the calcitonin gene by dexamethasone, a synthetic glucocorticoid. Northern blot analysis of total cellular RNA isolated from the TT cells showed hybridization of the calcitonin probe to 3600- and 1000-base RNA species. The CGRP probe hybridized to 3600- and 1050-base RNA species. Dexamethasone treatment (10(-9) to 10(-5) M) of TT cells (for 6 days) caused a dosage-dependent increase in calcitonin mRNA levels and a decrease in CGRP mRNA levels. These findings were confirmed in time course studies where dexamethasone treatment (10(-6) M) caused a 2-13-fold increase in calcitonin mRNA and a 40-60% decrease in CGRP mRNA between 4 and 6 days of treatment; the effect was reversible after dexamethasone withdrawal. After excluding an effect of dexamethasone on calcitonin and CGRP mRNA stability, we have concluded that dexamethasone affects the splicing mechanism to favor production of calcitonin mRNA over CGRP mRNA.