At develops in 2-5 of carriers, usually after more than 20 years
At develops in 2-5 of carriers, usually after more than 20 years of HTLV-1 latency [1,2]. Although it is a slow and multifactorial process, progression of ATL tightly correlates with high HTLV-1 proviral load [3]. Treatments for ATL are unspecific and unsatisfactory. Once developed, ATL is minimally treatable. In addition,* Correspondence: [email protected] 1 Department of Biochemistry, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong Full PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28151467 list of author information is available at the end of the articleprophylactic agents that can prevent the development of ATL in carriers of HTLV-1 remain to be identified [2]. Expression of HTLV-1 provirus is transcriptionally mediated through the viral transactivator Tax, which potently stimulates the activity of long terminal repeats (LTR) by activating the cellular transcription factor CREB and coactivators such as CREB-binding protein (CBP) and CREB-regulating transcriptional coactivators (CRTCs), also known as transducers of regulated CREB activity (TORCs) [4-9]. We have previously characterized the essential roles of Tax, CREB and CRTCs in this process [7,10,11]. Particularly, we have demonstrated the requirement of CRTCs in Tax activation of the LTR [7]. In addition to a viral LTR, a battery of cellular genes can also be activated by Tax primarily through CREB?2013 Tang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Tang et al. Retrovirology 2013, 10:40 http://www.retrovirology.com/content/10/1/Page 2 ofand NF-B. Tax is a major viral oncoprotein that plays a crucial role in the initiation of malignant transformation [12]. Tax also cooperates with other viral oncoproteins such as HBZ in later phases of leukemogenesis [13]. It has been generally accepted that activation of both CREB and NF-B by Tax is required for full-blown transformation [12]. Consistent with Tax playing an essential role in both viral transcription and oncogenesis, counteracting Tax function or eliminating Tax-expressing cells has shown anti-HTLV-1 and anti-ATL effects [14,15]. Thus, we hypothesized that identification of protein LY-2523355 site kinases that regulate Tax might reveal new strategies for disease prevention and intervention using small-molecule agonists and antagonists of such kinases. In searching for these kinases, we noticed that CRTCs are regulated by upstream kinases such as LKB1, AMP-activated protein kinases (AMPKs) and salt-inducible kinases (SIKs) [16-18]. LKB1 is a tumor suppressor inactivated in Peutz-Jeghers syndrome, a rare autosomal dominant disorder characterized by gastrointestinal polyps and a higher risk of malignancy [19]. LKB1 phosphorylates and activates AMPKs and AMPK-related kinases, which in turn phosphorylate CRTC2 at S171, leading to its association with 14-3-3 proteins and sequestration in the cytoplasm [16]. As such, AMPKs and SIKs are major kinases that regulate CRTCs [18,20]. However, the roles of LKB1, AMPKs and SIKs in Tax-mediated transcriptional activation remain elusive. In this study, we investigated the regulatory roles of LKB1, AMPKs and SIKs in Tax activation of the HTLV-1 LTR. We demonstrated LKB1 and SIKs to be negative regulators of HTLV-1 transcription. Our work suggests a new model in which LKB1 and SIKs suppress Ta.