Abstract
Tumour cells are frequently characterized by over-expression of the polypeptide chain initiation factor eIF4E and current evidence supports the view that this factor contributes to malignant transformation. The availability of eIF4E for protein synthesis is regulated by the 4E binding proteins. The ability of these proteins to bind eIF4E is inhibited by multi-site phosphorylation, catalysed by the mammalian target of rapamycin (mTOR) and other protein kinases. This phosphorylation is stimulated by growth factors and nutrients whereas dephosphorylation is activated by a variety of cellular stresses. Over-expression of eIF4E promotes resistance to apoptosis, most likely as a result of enhanced synthesis of growth-promoting and anti-apoptotic proteins. Conversely, increased levels of the 4E binding proteins can promote apoptosis and suppress tumourigenicity. Consistent with this, the mTOR inhibitor rapamycin can enhance cell death, especially in cells in which signal transduction pathways that activate mTOR are hyperactive, and analogues of rapamycin are now in clinical use against a number of human cancers. Recent evidence suggests that phosphorylation may also reduce the stability of the 4E binding proteins, as a consequence of increased susceptibility to ubiquitination and subsequent degradation. Such accelerated degradation would result in greater availability of eIF4E for translation and the inhibition of apoptosis.
Keywords: Cancer, mTOR, oncogene, protein phosphorylation, therapy, translational control
Current Cancer Therapy Reviews
Title: Control of Protein Synthesis in Malignant Transformation - the Role of eIF4E and the eIF4E Binding Proteins in the Regulation of Apoptosis
Volume: 3 Issue: 3
Author(s): Michael J. Clemens, Androulla Elia and Constantina Constantinou
Affiliation:
Keywords: Cancer, mTOR, oncogene, protein phosphorylation, therapy, translational control
Abstract: Tumour cells are frequently characterized by over-expression of the polypeptide chain initiation factor eIF4E and current evidence supports the view that this factor contributes to malignant transformation. The availability of eIF4E for protein synthesis is regulated by the 4E binding proteins. The ability of these proteins to bind eIF4E is inhibited by multi-site phosphorylation, catalysed by the mammalian target of rapamycin (mTOR) and other protein kinases. This phosphorylation is stimulated by growth factors and nutrients whereas dephosphorylation is activated by a variety of cellular stresses. Over-expression of eIF4E promotes resistance to apoptosis, most likely as a result of enhanced synthesis of growth-promoting and anti-apoptotic proteins. Conversely, increased levels of the 4E binding proteins can promote apoptosis and suppress tumourigenicity. Consistent with this, the mTOR inhibitor rapamycin can enhance cell death, especially in cells in which signal transduction pathways that activate mTOR are hyperactive, and analogues of rapamycin are now in clinical use against a number of human cancers. Recent evidence suggests that phosphorylation may also reduce the stability of the 4E binding proteins, as a consequence of increased susceptibility to ubiquitination and subsequent degradation. Such accelerated degradation would result in greater availability of eIF4E for translation and the inhibition of apoptosis.
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Michael J. Clemens , Androulla Elia and Constantina Constantinou , Control of Protein Synthesis in Malignant Transformation - the Role of eIF4E and the eIF4E Binding Proteins in the Regulation of Apoptosis, Current Cancer Therapy Reviews 2007; 3 (3) . https://dx.doi.org/10.2174/157339407781368323
DOI https://dx.doi.org/10.2174/157339407781368323 |
Print ISSN 1573-3947 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-6301 |
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argeted Protein Degradation is gaining momentum in cancer therapy, it facilitate targeting undruggable proteins, it overcome cancer resistance and avoid undesirable side effects. Thus small molecules degraders have emerged as novel therapeutic strategy. Targeted protein degradation (TPD), the process of eliminating a protein of interest hold a great promise for ...read more
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