Genome-wide expression changes induced by HTLV-1 Tax: evidence for MLK-3 mixed lineage kinase involvement in Tax-mediated NF-κB activation

Abstract

The Tax protein of human T-lymphotropic virus type 1 (HTLV-1), an oncoprotein that transactivates viral and cellular genes, plays a key role in HTLV-1 replication and pathogenesis. We used cDNA microarrays to examine Tax-mediated transcriptional changes in the human Jurkat T-cell lines JPX-9 and JPX-M which express Tax and Tax-mutant protein, respectively, under the control of an inducible promoter. Approximately 300 of the over 2000 genes examined were di erentially expressed in the presence of Tax. These genes were grouped according to their function and are discussed in the context of existing ®ndings in the literature. There was strong agreement between our results and genes previously reported as being Tax-responsive. Genes that were di erentially expressed in the presence of Tax included those related to apoptosis, the cell cycle and DNA repair, signaling factors, immune modulators, cytokines and growth factors, and adhesion molecules. Functionally, we provide evidence that one of these genes, the mixed-lineage kinase MLK-3, is involved in Tax-mediated NF-kB signaling. Our current results provide additional insights into Tax-mediated signaling. Oncogene (2001) 20, 4484 ± 4496.

Activation of NF-κB by HTLV-I and implications for cell transformation

“…The most notable viral regulatory protein is, however, the 40 kDa transactivator protein Tax (Jeang, 2001;Yoshida, 2001;Franchini et al, 2003). In addition to regulating viral gene expression through the 5 0 long terminal repeat (LTR), Tax induces or represses the expression of a large variety of cellular genes (Sun and Ballard, 1999;Ng et al, 2001). Consistently, emerging evidence suggests that Tax serves as the primary oncogenic mediator of HTLV-I (Franchini et al, 2003).…”

“…One example is the mixed-lineage kinase 3 (MLK-3) (Ng et al, 2001), a member of the MAP3K family with a known function in NF-kB activation (Hehner et al, 2000). At least under overexpression conditions, MLK-3 dominant-negative mutants inhibit Tax-stimulated NF-kB activation.…”

Molecular mechanisms of cellular transformation by HTLV-1 Tax

“…These changes include several factors with growth promoting and/or antiapoptotic functions whose expression patterns are modulated by Tax (Ng et al, 2001). Below, we summarize some salient examples (Figure 1).…”

Impact of HTLV-I Tax on cell cycle progression and the cellular DNA damage repair response

“…The DNA dependent protein kinase complex (DNA-PK) assembles from three distinct subunits, Ku70, Ku80 and the DNA-PK catalytic subunit and is thought to be the sensor and regulator element of DSB repair. Gene array studies revealed that Tax expressing cells display reduced levels of Ku80 mRNA as compared to controls (Ng et al, 2001), which could reduce the efficiency of DSB repair leading to an increased genomic mutation frequency. More studies will be needed to test this possibility.…”