Hijacking of the AP-1 Signaling Pathway during Development of ATL

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of a fatal malignancy known as adult T-cell leukemia (ATL). One way to address the pathology of the disease lies on conducting research with a molecular approach. In addition to the analysis of ATL-relevant signaling pathways, understanding the regulation of important and relevant transcription factors allows researchers to reach this fundamental objective. HTLV-1 encodes for two oncoproteins, Tax and HTLV-1 basic leucine-zipper factor, which play significant roles in the cellular transformation and the activation of the host's immune responses. Activating protein-1 (AP-1) transcription factor has been linked to cancer and neoplastic transformation ever since the first representative members of the Jun and Fos gene family were cloned and shown to be cellular homologs of viral oncogenes. AP-1 is a dimeric transcription factor composed of proteins belonging to the Jun (c-Jun, JunB, and JunD), Fos (c-Fos, FosB, Fra1, and Fra2), and activating transcription factor protein families. Activation of AP-1 transcription factor family by different stimuli, such as inflammatory cytokines, stress inducers, or pathogens, results in innate and adaptive immunity. AP-1 is also involved in various cellular events including differentiation, proliferation, survival, and apoptosis. Deregulated expression of AP-1 transcription factors is implicated in various lymphomas such as classical Hodgkin lymphomas, anaplastic large cell lymphomas, diffuse large B-cell lymphomas, and adult T-cell leukemia. Here, we review the current thinking behind deregulation of the AP-1 pathway and its contribution to HTLV-induced cellular transformation.

Keywords: AP-1; HBZ; HTLV-1; JunD; antisense transcription; leukemia.

FIGURE 1

Schematical presentation of the structure of AP-1 proteins. Activator protein 1 (AP-1) proteins include the JUN, FOS, activating transcription factor (ATF), and musculoaponeurotic fibrosarcoma (MAF) protein families, which can form homodimers and heterodimers through their leucine-zipper domains. The AP-1 proteins exhibit several domains, including the bZIP domain (leucine zipper plus basic domain), transactivation domains, and docking sites for several kinases, such as JNK or ERK. These kinases modulate the activity of those transcription factors by phosphorylation of serine and threonine residues.

FIGURE 2

Transcriptional and post-translational activation of AP-1. AP-1 activity is stimulated by external stimuli like growth factors or inflammatory cytokines and a complex network of kinase such as mitogen-activated protein kinases (MAPKs) of the extracellular-signal regulated kinase (ERK), p38, and JUN amino-terminal kinase (JNK) families. Posttranslational phosphorylation by various kinases regulates AP-1 activity, which includes its transactivating potential, DNA-binding capacity, and the stability of AP-1 components. GSK-3β, glycogen synthase kinase-3β; MAPKK, MAPK kinase; RSK2, ribosomal S6 kinase 2; TCF, ternary complex factor; SRE, serum-response element; TRE, TPA-responsive element; CRE, cAMP-response element; SIE, Sis-inducible element.

FIGURE 3

Mechanisms of Tax activation of AP-1 pathway. Pathways upstream of AP-1 are normally activated in response to external stimuli whereas presence of Tax overrides this requirement. Indeed Tax is able to activate the Akt/PI3K pathway as well as the SRF pathways thus activating at the transcription of c-Fos, Fra-1, c-Jun, JunB, and JunD genes. By interacting with the JNK inhibitor G-protein pathway suppressor 2 (GPS2), Tax also participate to the exhibited highly activity of AP-1 in HTLV-1 infected cells through a constitutive activation of JNK (Jin et al., 1997). Interestingly, AP-1 proteins such as c-Jun and c-Fos activate the transcription through the 21 bp repeat in HTLV-1 LTR.

FIGURE 4

Differential effects of HBZ on the Jun family proteins. HBZ specifically interacted with all three members of the Jun Family (JunB, c-Jun, and JunD), but it regulates differently the transcriptional properties of the Jun family. HBZ dramatically suppressed c-Jun- and JunB-induced transcriptional activation from the AP-1 element by sequestering c-Jun and JunB into HBZ-NB and by decreasing the steady-state level of c-Jun and the stability of c-Jun protein in cells through a proteasome-dependent pathway. It is particularly interesting to note that HBZ has a different and opposite action on JunD expression. HBZ can stimulate the transcription of JunD and by nuclear retention of RPS25, HBZ allows the expression of an alternative isoform of JunD called ΔJunD. Furthermore, HBZ cooperates with JunD and sp1 to enhance transcription of the 3′-LTR and also the human telomerase reverse transcriptase gene (hTERT).