Anti-Apoptotic Effect of Tax: An NF-κB Path or a CREB Way?

Daniela Saggioro

doi:10.3390/v3071001

Abstract

The NF-κB pathway is intimately linked to the survival of mammalian cells, and its activation by Tax has consequently been considered important for human T-cell leukemia/lymphoma virus type 1 (HTLV-1)-infected cell resistance to death. Very little emphasis has been given to other mechanisms, although Tax regulates the expression and activity of several cellular genes. The finding that CREB protein is activated in HTLV-1 infected cells underlines the possibility that other mechanisms of survival may be implicated in HTLV-1 infection. Indeed, CREB activation or overexpression plays a role in normal hematopoiesis, as well as in leukemia development, and CREB is considered as a survival factor in various cell systems. A better understanding of the different molecular mechanisms used by Tax to counteract cell death will also help in the development of new therapeutic strategies for HTLV-1 associated diseases.

Highlights

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of a highly aggressive and fatal disease called adult T-cell leukemia/lymphoma (ATLL) [1,2]
We have shown that induction of a specific block in CREB transactivation using dominant negative CREB mutants increased apoptosis, whilst triggering CREB phosphorylation with forskolin reduced apoptosis [108]
In agreement with our results, Kim et al [109] observed higher levels of intracellular p-CREB in a panel of HTLV-1-infected versus uninfected T cell lines. They demonstrated that Tax expression was directly involved in the enhanced CREB phosphorylation. These findings suggest that the virus has evolved a mechanism to elevate pCREB levels in the HTLV-1-infected cells, likely as a way to promote strong Tax-mediated transactivation of CREB-responsive genes

Summary

Introduction

The human T-cell leukemia/lymphoma virus type 1 (HTLV-1) is the etiological agent of a highly aggressive and fatal disease called adult T-cell leukemia/lymphoma (ATLL) [1,2]. The intrinsic apoptotic pathway requires pro-apoptotic proteins of the Bcl-2 family which act principally at the mitochondrial level. Activation of these proteins by apoptotic signals leads to changes in mitochondrial outer membrane permeability, release of cytochrome c, and activation of the initiator caspase 9 through the formation of the apoptosome. Both pathways induce activation of executioner caspases, and subsequent controlled destruction of cells. In this review we will briefly discuss new findings and our current understanding of how the NK- B, PI3K/Akt, Ras/Raf/ERK pathways, and CREB activation, are engaged by Tax to overcome cell death

NF- B Pathway

CREB Activation

Conclusions