Transcriptional repression of the RET proto-oncogene by a mitogen activated protein kinase-dependent signalling pathway.

Scott Andrew, Amanda Capes-Davis, Patric J Delhanty, Deborah J Marsh, Lois M Mulligan, Bruce G Robinson

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

Abstract

Transcription factors play important roles in regulating cell growth and differentiation. In this study, treatment of the MTC cell line, TT, with phorbol 12-myristate 13-acetate (PMA) was shown to reduce neurite outgrowth which may be associated with de-differentiation and loss of the transformed phenotype. Northern blotting revealed that PMA transiently induced early growth response gene 1 (Egr-1) expression and decreased RET expression. Transient transfection analyses using 5'-deletion constructs of the basal RET promoter, demonstrated the requirement of a region between '70 and '33 bp for PMA-inducible expression. Gel shift and supershift studies demonstrated that PMA induced Egr-1 formed part of a complex capable of binding to the RET minimal promoter. Overexpression of Egr-1 displaced both sephacryl and phosphocellulose protein 1 (Sp1) and Sp3 from a GC-box element previously found to be important for RET basal expression. Furthermore, use of a raf-1 inducible TT cell line, that has been previously shown to downregulate RET expression, revealed that this downregulation may be linked to the induction of Egr-1. Our data suggest that regulation of RET expression during development and in medullary thyroid carcinoma may be determined, at least in part, by this complex of Sp and Egr-1 proteins.
Original languageEnglish
Pages (from-to)9-19
Number of pages11
JournalGene
Volume298
Issue number1
DOIs
Publication statusPublished - 2002

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