Abstract
Previously, we demonstrated that the abnormal accumulation of Cu in Menkes disease (MD) fibroblasts (Fb) is associated with an increased amount of metallothionein (MT) (2-3 times normal) (Pediat. Res., in press). To define the basic defect in MD, we investigated the effect of varying concentrations of extracellular Cu (exCu) on the regulation of CuMT metabolism informal (N) and MD Fb. Relative levels of MT were measured by 35S-cysteine incorporation into the 10,000 MW Cu-binding cytosolic protein. Total intracellular Cu was measured by atomic absorption spectrometry. After exposure of N and MD Fb to 2 ug/ml Cu (as CuCl2) maximal levels of MT synthesis were attained within 8 h and remained elevated for at least 56 h. Additional Cu (up to 20 ug/ml) did not increase the rate of MT synthesis above that observed with 2 ug/ml. Pulse-chase experiments demonstrated no difference in the half-life (T1/2=48-60 h) of MTs in N or MD Fb in the presence or absence of exCu. These results demonstrated that MT was an inducible protein in both N and MD Fb. Also, the rate of degradation of the MTs was the same in both the N and MD Fb. Although the mechanism of MT induction by exCu appears normal in MD Fb, the suppression of MT synthesis in the absence of excess Cu may be defective. This regulatory defect results in abnormally high constitutive levels of MT in MD Fb. Whether this defect in regulation of MT synthesis is transcriptional or translational is currently under investigation.
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Labadie, G., Hirschhorn, K. & Beratis, N. 736 EFFECT OF EXTRACELLULAR COPPER (Cu) ON METALLOTHIONEIN METABOLISM IN NORMAL AND MENKES FIBROBLASTS. Pediatr Res 15 (Suppl 4), 565 (1981). https://doi.org/10.1203/00006450-198104001-00759
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DOI: https://doi.org/10.1203/00006450-198104001-00759