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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
Author(s) -
Meng Zheng,
Jackson Nateka L.,
Choi Hyoungsoo,
King Peter H.,
Emanuel Peter D.,
Blume Scott W.
Publication year - 2008
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.21486
Subject(s) - internal ribosome entry site , untranslated region , translational regulation , biology , translation (biology) , eukaryotic translation , repressor , messenger rna , open reading frame , five prime untranslated region , ribosome , microbiology and biotechnology , rna , gene expression , genetics , gene , peptide sequence
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. © 2008 Wiley‐Liss, Inc.