Department of Biochemistry, The University of Hong Kong, 21 Sassoon Road, Pokfulam, Hong Kong.
Retrovirology. 2013 Apr 11;10:40. doi: 10.1186/1742-4690-10-40.
Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia (ATL). Treatment options are limited and prophylactic agents are not available. We have previously demonstrated an essential role for CREB-regulating transcriptional coactivators (CRTCs) in HTLV-1 transcription.
In this study we report on the negative regulatory role of LKB1 tumor suppressor and salt-inducible kinases (SIKs) in the activation of HTLV-1 long terminal repeats (LTR) by the oncoprotein Tax. Activation of LKB1 and SIKs effectively blunted Tax activity in a phosphorylation-dependent manner, whereas compromising these kinases, but not AMP-dependent protein kinases, augmented Tax function. Activated LKB1 and SIKs associated with Tax and suppressed Tax-induced LTR activation by counteracting CRTCs and CREB. Enforced expression of LKB1 or SIK1 in cells transfected with HTLV-1 molecular clone pX1MT repressed proviral transcription. On the contrary, depletion of LKB1 in pX1MT-transfected cells and in HTLV-1-transformed T cells boosted the expression of Tax. Treatment of HTLV-1 transformed cells with metformin led to LKB1/SIK1 activation, reduction in Tax expression, and inhibition of cell proliferation.
Our findings revealed a new function of LKB1 and SIKs as negative regulators of HTLV-1 transcription. Pharmaceutical activation of LKB1 and SIKs might be considered as a new strategy in anti-HTLV-1 and anti-ATL therapy.
人类 T 细胞白血病病毒 1 型（HTLV-1）可导致成人 T 细胞白血病（ATL）。目前的治疗选择有限，且尚无预防性药物。我们之前已经证明了 CREB 调节转录共激活因子（CRTCs）在 HTLV-1 转录中的重要作用。
在这项研究中，我们报告了 LKB1 肿瘤抑制因子和盐诱导激酶（SIKs）在致癌蛋白 Tax 激活 HTLV-1 长末端重复序列（LTR）中的负调控作用。LKB1 和 SIKs 的激活以磷酸化依赖的方式有效地削弱了 Tax 的活性，而削弱这些激酶（而非 AMP 依赖性蛋白激酶）则增强了 Tax 的功能。激活的 LKB1 和 SIKs 与 Tax 结合，并通过拮抗 CRTCs 和 CREB 来抑制 Tax 诱导的 LTR 激活。在转染 HTLV-1 分子克隆 pX1MT 的细胞中过表达 LKB1 或 SIK1 会抑制前病毒转录。相反，在转染了 pX1MT 的细胞和 HTLV-1 转化的 T 细胞中耗尽 LKB1 会增强 Tax 的表达。二甲双胍处理 HTLV-1 转化细胞会导致 LKB1/SIK1 激活、Tax 表达减少和细胞增殖抑制。
我们的发现揭示了 LKB1 和 SIKs 作为 HTLV-1 转录负调节剂的新功能。LKB1 和 SIKs 的药物激活可能被视为抗 HTLV-1 和抗 ATL 治疗的新策略。
