Transcriptional and translational control of ornithine decarboxylase during Ras transformation

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

ODC (ornithine decarboxylase) activity is induced following ras activation. However, the Ras effector pathways responsible are unknown. These experiments used NIH-3T3 cells expressing partial-loss-of-function Ras mutants to activate selectively pathways downstream of Ras and examined the contribution of each pathway to ODC induction. Overexpression of Ras 12V, a constitutively active mutant, resulted in ODC activities up to 20-fold higher than controls. Stable transfections of Ras partial-loss-of-function mutants and constitutively active forms of MEK (MAPK kinase) and Akt indicated that activation of more than one Ras effector pathway is necessary for the complete induction of ODC activity. The increase in ODC activity in Ras 12V-transformed cells is not owing to a substantial change in ODC protein half-life, which increased by < 2-fold. Northern-blot analysis and reporter assays suggested that the mechanism of ODC induction involves both a modest increase in the transcription of ODC mRNA and a much more considerable increase in the translation of mRNA into protein. ODC transcription was controlled through a pathway dependent on Raf/MEK/ERK (where ERK stands for extracellular-signal-regulated kinase) activation, whereas activation of the phosphoinositide 3-kinase and the Raf/MEK/ERK pathways were necessary for translational regulation of ODC. The increase in ODC synthesis was accompanied by changes in phosphorylation of eukaryotic initiation factor 4E and its binding protein 4E-BP1. Results show that the phosphoinositide 3-kinase pathway regulates phosphorylation of both proteins, whereas the Raf/MEK/ERK pathway affects only the eukaryotic initiation factor 4E phosphorylation.

Original languageEnglish (US)
Pages (from-to)257-264
Number of pages8
JournalBiochemical Journal
Volume377
Issue number1
DOIs
StatePublished - Jan 1 2004

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Ornithine Decarboxylase
Mitogen-Activated Protein Kinase Kinases
Phosphorylation
Chemical activation
Eukaryotic Initiation Factor-4E
1-Phosphatidylinositol 4-Kinase
MAP Kinase Signaling System
Transcription
Phosphatidylinositols
raf Kinases
MAP Kinase Kinase Kinases
NIH 3T3 Cells
Messenger RNA
Proteins
Extracellular Signal-Regulated MAP Kinases
Protein Biosynthesis
Northern Blotting
Transfection
Half-Life
Assays

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

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abstract = "ODC (ornithine decarboxylase) activity is induced following ras activation. However, the Ras effector pathways responsible are unknown. These experiments used NIH-3T3 cells expressing partial-loss-of-function Ras mutants to activate selectively pathways downstream of Ras and examined the contribution of each pathway to ODC induction. Overexpression of Ras 12V, a constitutively active mutant, resulted in ODC activities up to 20-fold higher than controls. Stable transfections of Ras partial-loss-of-function mutants and constitutively active forms of MEK (MAPK kinase) and Akt indicated that activation of more than one Ras effector pathway is necessary for the complete induction of ODC activity. The increase in ODC activity in Ras 12V-transformed cells is not owing to a substantial change in ODC protein half-life, which increased by < 2-fold. Northern-blot analysis and reporter assays suggested that the mechanism of ODC induction involves both a modest increase in the transcription of ODC mRNA and a much more considerable increase in the translation of mRNA into protein. ODC transcription was controlled through a pathway dependent on Raf/MEK/ERK (where ERK stands for extracellular-signal-regulated kinase) activation, whereas activation of the phosphoinositide 3-kinase and the Raf/MEK/ERK pathways were necessary for translational regulation of ODC. The increase in ODC synthesis was accompanied by changes in phosphorylation of eukaryotic initiation factor 4E and its binding protein 4E-BP1. Results show that the phosphoinositide 3-kinase pathway regulates phosphorylation of both proteins, whereas the Raf/MEK/ERK pathway affects only the eukaryotic initiation factor 4E phosphorylation.",
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Transcriptional and translational control of ornithine decarboxylase during Ras transformation. / Shantz, Lisa M.

In: Biochemical Journal, Vol. 377, No. 1, 01.01.2004, p. 257-264.

Research output: Contribution to journalArticle

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