Alterations in RNA‐binding activities of IRES‐regulatory proteins as a mechanism for physiological variability and pathological dysregulation of IGF‐IR translational control in human breast tumor cells
- 1 May 2008
- journal article
- research article
- Published by Wiley in Journal of Cellular Physiology
- Vol. 217 (1), 172-183
- https://doi.org/10.1002/jcp.21486
Abstract
The type I insulin-like growth factor receptor (IGF-IR) is integrally involved in the control of cellular proliferation and survival. An internal ribosomal entry site (IRES) within the 1,038 nucleotide 5′-untranslated region of the human IGF-IR mRNA helps to provide the tight control of IGF-IR expression necessary for maintenance of normal cellular and tissue homeostasis. The IRES maps to a discrete sequence of 85 nucleotides positioned just upstream of the IGF-IR initiation codon, allowing the ribosome to bypass the highly structured regions of the 5′-UTR as well as the upstream open reading frame. The authenticity of the IGF-IR IRES has been confirmed by its sensitivity to deletion of the promoter from a bicistronic reporter construct, and its resistance in a monocistronic reporter construct to co-expression of a viral 2A protease. We previously characterized HuR as a potent repressor of IGF-IR translation. Here we demonstrate that hnRNP C competes with HuR for binding the IGF-IR 5′-UTR and enhances IRES-mediated translation initiation in a concentration-dependent manner. We observed changes in binding of hnRNP C versus HuR to the IGF-IR 5′-UTR in response to physiological alterations in cellular environment or proliferative status. Furthermore, we have found distinct alterations in the pattern of protein binding to the IGF-IR 5′-UTR in human breast tumor cells in which IGF-IR IRES activity and relative translational efficiency are aberrantly increased. These results suggest that dysregulation of the IGF-IR IRES through changes in the activities of RNA-binding translation-regulatory proteins could be responsible for IGF-IR overexpression in a proportion of human breast tumors. J. Cell. Physiol. 217: 172–183, 2008.Keywords
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