Translational and post-translational modifications of proteins as a new mechanism of action of alpha-interferon: review article.
Interferon-alpha (IFNalpha) is a recombinant protein widely used in the therapy of several neoplasms such as myeloma, renal cell carcinoma, epidermoid cervical and head and neck tumours and melanoma. IFNalpha, the first cytokine to be produced by recombinant DNA technology, has emerged as an important regulator of cancer cell growth and differentiation, affecting cellular communication and signal transduction pathways. However, the way by which tumour cell growth is directly suppressed by IFNalpha is not well known. Wide evidence exists on the possibility that cancer cells undergo apoptosis after the exposure to the cytokine. Here we will discuss data obtained by us and others on the post-translational regulation of the expression of proteins involved in the occurrence of apoptotic process such as tissue transglutaminase (tTG) or in the modulation of cell cycle such as the cyclin-dependent kinase inhibitor p27. This new way of regulation of p27 and tTG occurs through the modulation of their proteasome-dependent degradation induced by the cytokine. We will also review the involvement of protein synthesis machinery in the induction of cell growth inhibition by IFNalpha. In details, we will describe the effects of IFNalpha on the expression and activity of the protein kinase dependent from dsRNA (PKR) and on the eukaryotic initiation factor of protein synthesis 5A (eIF-5A) and their correlations with the regulation of cancer cell growth. These data strongly suggest that the antitumour activity of IFNalpha against human tumours could involve still unexplored mechanisms based on post-translational and translational control of the expression of proteins that regulate cell proliferation and apoptosis.
Dipartimento di Biochimica e Biofisica, Seconda Università di Napoli, Naples, Italy. michele.caraglia@unina2.it
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Caraglia
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Vitale
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Marra
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Del Prete
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Lentini
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Budillon
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Beninati
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Abbruzzese
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism*; D010448:Peptide Initiation Factors / Q000378:metabolism; D046188:Protein Modification, Translational; D011499:Protein Processing, Post-Translational; D016601:RNA-Binding Proteins / Q000378:metabolism; D017471:Receptors, Interferon / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D019892:eIF-2 Kinase / Q000378:metabolism; D000097574:Eukaryotic Translation Initiation Factor 5A
D016898:Interferon-alpha; D010448:Peptide Initiation Factors; D016601:RNA-Binding Proteins; D017471:Receptors, Interferon; D019892:eIF-2 Kinase; D000097574:Eukaryotic Translation Initiation Factor 5A