[Frontiers in Bioscience 14, 3338-3351, January 1, 2009]

Control of cell death pathways by HTLV-1 proteins

Daniela Saggioro1, Micol Silic-Benussi2, Roberta Biasiotto2, Donna M. D'Agostino1,2, Vincenzo Ciminale1,2

1Molecular Immunology and Oncology Unit, Istituto Oncologico Veneto-IRRCS, via Gattamelata 64, I-35128 Padova, Italy, 2Department of Oncology and Surgical Sciences, University of Padova, via Gattamelata 64, I-35128 Padova, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Cell death in T-cell homeostasis
4. ATLL- increased proliferation, increased survival, or both?
5. Influence of individual viral proteins on cell death pathways
5.1. The Tax oncoprotein
5.1.1. Tax and the NF-kappaB pathway
5.1.2. Tax and the CREB pathway
5.1.3. Tax and AKT
5.1.4. Tax and tumor suppressor pathways
5.1.5. Tax and activation-induced cell death
5.2. The viral accessory proteins
5.2.1. Interactions of p13 with mitochondria
5.2.2. p12, T-cell activation, and calcium signalling
6. Conclusions and perspectives
7. Acknowledgements
8. References

1. ABSTRACT

Individuals infected with HTLV-1 harbor the virus mainly in CD4+ memory T-cells as a lifelong infection that remains subclinical in the majority of cases. However, about 3-5% of HTLV-1-infected individuals develop an aggressive T-cell neoplasia (ATLL) or a neurodegenerative disease (TSP/HAM) after a latency period ranging from years to decades. This review summarizes the current knowledge of the effects of the HTLV-1 proteins Tax, p13 and p12 on cell death and survival pathways. Tax, the major oncogenic determinant of HTLV-1, enhances cell survival through its effects on the NF-kappaB, CREB and AKT pathways and on the tumor suppressors p53 and Rb. p13 is targeted to the inner mitochondrial membrane and sensitizes cells to the Fas/ceramide apoptotic pathway and reactive oxygen species-mediated cell death. p12 enhances release of calcium from the endoplasmic reticulum and therefore may influence calcium-dependent apoptotic signals, including opening of the mitochondrial permeability transition pore. The long-term fate of HTLV-1-infected cells (apoptosis, survival, transformation) may therefore depend on the balance of the effects of Tax, p13 and p12 on cell death pathways.