Journal Article

Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications

Yulia Tabakin-Fix, Inbal Azran, Yana Schavinky-Khrapunsky, Oren Levy and Mordechai Aboud

in Carcinogenesis

Volume 27, issue 4, pages 673-681
Published in print April 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI:
Functional inactivation of p53 by human T-cell leukemia virus type 1 Tax protein: mechanisms and clinical implications

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Human T-cell leukemia virus type 1 (HTLV-I) has been implicated with the etiology of adult T-cell leukemia (ATL) and certain other clinical disorders. Although the leukemogenic mechanism of HTLV-1 is not fully understood yet, the viral Tax protein is widely regarded as a key factor in this mechanism. Tax can modulate the synthesis or function of many regulatory factors which control a wide range of normal and oncogenic cellular processes and therefore, it acts as a potent oncoprotein. In the last few years, special attention has been attracted to Tax interference with the transactivation function of p53, a tumor-suppressor protein that is involved in regulation of the cell-cycle and apoptosis and in maintaining the cellular genome integrity. p53 is mutated in ∼60% of all human tumors. In contrast, mutant p53 is found in only small percentage of ATL patients. Nevertheless, p53 is inactive in the leukemic cells of most ATL patients and in most HTLV-1 transformed cells. By inactivating p53, Tax can immortalize the HTLV-1-infected cells and destabilize their genome. Consequently, such cells can progress toward the ultimate leukemic state by a stepwise accumulation of oncogenic mutations and other types of chromosomal aberrations. Furthermore, since p53 exists in most ATL patients in its wild-type form, its reactivation by therapeutic drugs might be an effective approach for ATL therapy. Several mechanisms have been proposed so far for Tax-induced p53 inactivation. Understanding the exact mechanism of this Tax effect is essential for designing effective means for this therapeutic approach. In this review article, we discuss the various mechanisms proposed for Tax interference with p53 functions and their clinical and therapeutic implications.

Keywords: ATF, activating transcription factor; ATL, adult T-cell leukemia/lymphoma; CAF, CBP associated factor; CBP, CREB-binding protein; CREB, cAMP response element binding protein; HTLV-1, Human T-cell leukemia virus type 1; IκBα, inhibitor of NF-κB alpha; IKK, IκB kinase; IL-2, interleukin 2; NEMO, NF-κB essential modulator; NF-κB, nuclear factor kappa B; p65-KO MEF, p65(RelA)-knocked out mouse embryo fibroblasts; STLV-1, simian T-lymphotropic virus type 1

Journal Article.  8036 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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