Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways

Authors

Sofia Origanti, Marquette UniversityFollow
Lisa M. Shantz, Penn State College of MedicineFollow

Document Type

Article

Language

eng

Format of Original

9 p.

Publication Date

5-2007

Publisher

American Association for Cancer Research

Source Publication

Cancer Research

Source ISSN

0008-5472

Abstract

Ornithine decarboxylase (ODC) is the first and generally rate-limiting enzyme in polyamine biosynthesis. Deregulation of ODC is critical for oncogenic growth, and ODC is a target of Ras. These experiments examine translational regulation of ODC in RIE-1 cells, comparing untransformed cells with those transformed by an activated Ras12V mutant. Analysis of the ODC 5′ untranslated region (5′UTR) revealed four splice variants with the presence or absence of two intronic sequences. All four 5′UTR species were found in both cell lines; however, variants containing intronic sequences were more abundant in Ras-transformed cells. All splice variants support internal ribosome entry site (IRES)–mediated translation, and IRES activity is markedly elevated in cells transformed by Ras. Inhibition of Ras effector targets indicated that the ODC IRES element is regulated by the phosphorylation status of the translation factor eIF4E. Dephosphorylation of eIF4E by inhibition of mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) or the eIF4E kinase Mnk1/2 increases ODC IRES activity in both cell lines. When both the Raf/MEK/ERK and phosphatidylinositol 3-kinase/mammalian target of rapamycin pathways are inhibited in normal cells, ODC IRES activity is very low and cells arrest in G₁. When these pathways are inhibited in Ras-transformed cells, cell cycle arrest does not occur and ODC IRES activity increases, helping to maintain high ODC activity.

Comments

Accepted version. Cancer Research, Vol. 67, No. 10 (May 2007): 4834-4842. DOI. © 2007 American Association for Cancer Research. Used with permission.

Sofia Origanti was affiliated with Penn State College of Medicine at the time of publication.

Recommended Citation

Origanti, Sofia and Shantz, Lisa M., "Ras Transformation of RIE-1 Cells Activates Cap-Independent Translation of Ornithine Decarboxylase: Regulation by the Raf/MEK/ERK and Phosphatidylinositol 3-Kinase Pathways" (2007). Biological Sciences Faculty Research and Publications. 434.
https://epublications.marquette.edu/bio_fac/434