Abstract
HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-kappaB and CREB (cAMP-response element-binding protein)/ATF. Transforming growth factor-beta-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-kappaB. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-kappaB.
Highlights
Human T-cell lymphotropic virus type 1 (HTLV-1)2 is known as the cause of adult T-cell leukemia/lymphoma (ATLL)
We have reported that phosphorylation at Thr-187 is essential for Transforming growth factor--activated kinase 1 (TAK1) activation, and TAK1-binding protein 1 (TAB1) and TAK1-binding protein 2 (TAB2) are important for inducing phosphorylation [18]
In the present study, enhanced phosphorylation of p65 was observed in Tax-positive cells, suggesting that p65 phosphorylation will be a useful marker for detecting the constitutive activation of NF-B in cancer cells
Summary
Constitutive Activation of TAK1 by HTLV-1 Tax-dependent Overexpression of TAB2 Induces Activation of JNK-ATF2 but Not IKK-NF-B*. HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-B and CREB (cAMP-response element-binding protein)/ATF. ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-B. TAB2 functions as an adaptor protein to recruit TAK1 to TRAF2 (TNF-␣ receptor-associated factor) and TRAF6 in the TNF-␣ and interleukin-1 signaling pathways, respectively [8, 11, 13]. The present study investigated whether TAK1 is involved in Tax-dependent NF-B activation and other signaling pathways in HTLV-1-transformed cells
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