Glucocorticoids differentially inhibit expression of the RET proto-oncogene.
The RET proto-oncogene encodes a receptor tyrosine kinase activated by the binding of factors from the glial cell line-derived neurotrophic factor (GDNF) family to receptor-alpha components such as GDNF family receptor alpha-1 (GFR alpha-1). Mutations within the sequence of the RET proto-oncogene are associated with multiple endocrine neoplasia type 2 (MEN 2), an inherited tumor syndrome characterized by the development of medullary thyroid carcinoma (MTC) and other neuroendocrine tumors. Despite Northern analysis showing that RET is expressed in the majority of MTCs, the factors regulating this expression are poorly understood. To address this issue we examined RET expression in response to glucocorticoids in the TT cell line, derived from a metastatic MTC. The synthetic glucocorticoid dexamethasone was found to reduce RET expression at both mRNA and protein levels. This effect was dose responsive and maximal at 24 h. The reduction in RET mRNA was shown to be specific to glucocorticoids and was also seen in a primary MTC culture. Nuclear run-on studies revealed the reduction in steady-state RNA to be due to a decrease in RET mRNA transcription and the effect was shown to be independent of new protein synthesis or RNA stability. Dexamethasone was also found to exert an inhibitory effect upon cell growth, suggesting a potential use for glucocorticoids in the treatment of medullary carcinoma and MEN 2.
Capes-Davis
A
A
Kolling Institute of Medical Research and Department of Endocrinology, Royal North Shore Hospital, University of Sydney, N.S.W., Australia.
Andrew
S D
SD
Hyland
V J
VJ
Twigg
S
S
Learoyd
D L
DL
Dwight
T
T
Marsh
D J
DJ
Robinson
B G
BG
D018276:Carcinoma, Medullary / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D003907:Dexamethasone / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D029721:Drosophila Proteins; D015972:Gene Expression Regulation, Neoplastic; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005938:Glucocorticoids / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D011282:Pregnenediones / Q000494:pharmacology; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013256:Steroids / Q000378:metabolism / Q000494:pharmacology; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured
D029721:Drosophila Proteins; C494987:GFRA1 protein, human; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D005938:Glucocorticoids; C000715470:MAS1 protein, human; D011282:Pregnenediones; D000090063:Proto-Oncogene Mas; D011518:Proto-Oncogene Proteins; D013256:Steroids; C020175:16 alpha-ethyl-21-hydroxy-19-nor-4-pregnene-3,20-dione; D003907:Dexamethasone; D051096:Proto-Oncogene Proteins c-ret; D020794:Receptor Protein-Tyrosine Kinases; C416649:Ret protein, Drosophila