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.

Endogenous interaction profiling identifies DDX5 as an oncogenic coactivator of transcription factor Fra-1

“…Moreover, AP-1 transcription factors have essential effects on various cellular processes, such as proliferation, differentiation, apoptosis and inflammation [146,147,154]. A variety of cellular stimulation, including growth factors, cytokines, UV radiation, bacterial and viral infection and cellular stress, is able to regulate AP-1 transcriptional activity [147]. The dimer composition is critical to regulate activity of AP-1 proteins resulting in regulation of specific target genes [142].…”

“…Overexpression of Jun family members is found in many human cancers [142,147,170]. The expression of c-Jun plays an important role in tumor development, such as in liver, skin and breast tumors [146,171].…”

Integrated Omics Reveals Tollip as an Regulator and Therapeutic Target for Hepatic Ischemia‐Reperfusion Injury in Mice

“…C). The inactivation of MAPK signaling, as indicated by mRNA expression of Jun proto‐oncogene, AP‐1 transcription factor subunit ( Jun ), Fos proto‐oncogene, AP‐1 transcription factor subunit ( Fos ), and activating transcription factor 2 ( Atf2 ), in the Tollip deficiency group was further validated by quantitative real‐time PCR assay in the livers from mice subjected to IR insult for 6 hours (Fig. D).…”

Activator protein-1 transactivation of the major immediate early locus is a determinant of cytomegalovirus reactivation from latency

“…Elucidating the precise biological mechanism could indeed reveal potential therapeutic targets one could exploit to prevent viral reactivation. Two pathways that activate AP-1, Src-ERK (41) and PI3K/Akt (42), are already implicated in HCMV reactivation (17, 20) and are therefore potential candidates for further investigation. As a potent signaling molecule, US28 is an attractive, latently expressed viral protein capable of modulating cellular signaling pathways such as these.…”