Ras oncogene induces β-galactoside α2,6-sialytransferase (ST6Gal I) via a RalGEF-mediated signal to its housekeeping promoter

Abstract : Several oncogenic proteins are known to influence cellular glycosylation. In particular, transfection of codon 12 point mutated H-Ras increases CMP-Neu5Ac: Galbeta1,4GlcNAc alpha2,6-sialyltransferase I (ST6Gal I) activity in rodent fibroblasts. Given that Ras mediates its effects through at least three secondary effector pathways (Raf, RalGEFs and PI3K) and that transcriptional control of mouse ST6Gal I is achieved by the selective use of multiple promoters, we attempted to identify which of these parameters are involved in linking the Ras signal to ST6Gal I gene transcription in mouse fibroblasts. Transformation by human K-Ras or H-Ras (S12 and V12 point mutations, respectively) results in a 10-fold increase in ST6Gal I mRNA, but no alteration in the expression of related sialyltransferases. Using an inducible H-RasV12 expression system, a direct causal link between activated H-Ras expression and elevated ST6Gal I mRNA was demonstrated. The accumulation of the ST6Gal I transcript in response to activated Ras was accompanied by an increase of alpha2,6-sialyltransferase activity and of Neu5Acalpha2,6Gal at the cell surface. Results obtained with H-RasV12 partial loss of function mutants H-RasV12S35 (Raf signal only), H-RasV12C40 (PI3-kinase signal only) and H-RasV12G37 (RalGEFs signal only) suggest that the H-Ras induction of the mouse ST6Gal I gene (Siat1) transcription is primarily routed through RalGEFs. 5'-Rapid amplification of cDNA ends analysis demonstrated that the increase in ST6Gal I mRNA upon H-RasV12 or K-RasS12 transfection is mediated by the Siat1 housekeeping promoter P3-associated 5' untranslated exons.
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M. Dalziel, F. Dall'Olio, A. Mungul, V. Piller, F. Piller. Ras oncogene induces β-galactoside α2,6-sialytransferase (ST6Gal I) via a RalGEF-mediated signal to its housekeeping promoter. European Journal of Biochemistry, Wiley, 2004, 271 (18), pp.3623-3634. ⟨10.1111/j.1432-1033.2004.04284.x⟩. ⟨hal-00112974⟩



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