Department of Microbiology and Immunology, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA.
PLoS Pathog. 2011 Apr;7(4):e1002025. doi: 10.1371/journal.ppat.1002025. Epub 2011 Apr 28.
Activation of I-κB kinases (IKKs) and NF-κB by the human T lymphotropic virus type 1 (HTLV-1) trans-activator/oncoprotein, Tax, is thought to promote cell proliferation and transformation. Paradoxically, expression of Tax in most cells leads to drastic up-regulation of cyclin-dependent kinase inhibitors, p21(CIP1/WAF1) and p27(KIP1), which cause p53-/pRb-independent cellular senescence. Here we demonstrate that p21(CIP1/WAF1)-/p27(KIP1)-mediated senescence constitutes a checkpoint against IKK/NF-κB hyper-activation. Senescence induced by Tax in HeLa cells is attenuated by mutations in Tax that reduce IKK/NF-κB activation and prevented by blocking NF-κB using a degradation-resistant mutant of I-κBα despite constitutive IKK activation. Small hairpin RNA-mediated knockdown indicates that RelA induces this senescence program by acting upstream of the anaphase promoting complex and RelB to stabilize p27(KIP1) protein and p21(CIP1/WAF1) mRNA respectively. Finally, we show that down-regulation of NF-κB by the HTLV-1 anti-sense protein, HBZ, delay or prevent the onset of Tax-induced senescence. We propose that the balance between Tax and HBZ expression determines the outcome of HTLV-1 infection. Robust HTLV-1 replication and elevated Tax expression drive IKK/NF-κB hyper-activation and trigger senescence. HBZ, however, modulates Tax-mediated viral replication and NF-κB activation, thus allowing HTLV-1-infected cells to proliferate, persist, and evolve. Finally, inactivation of the senescence checkpoint can facilitate persistent NF-κB activation and leukemogenesis.
人类 T 淋巴细胞白血病病毒 1（HTLV-1）转激活蛋白/癌蛋白 Tax 激活 IκB 激酶（IKK）和 NF-κB，被认为可促进细胞增殖和转化。矛盾的是，Tax 在大多数细胞中的表达导致细胞周期蛋白依赖性激酶抑制剂 p21（CIP1/WAF1）和 p27（KIP1）的急剧上调，导致 p53-/pRb 非依赖性细胞衰老。在这里，我们证明 p21（CIP1/WAF1）/p27（KIP1）介导的衰老构成了对 IKK/NF-κB 过度激活的检查点。Tax 在 HeLa 细胞中诱导的衰老可通过降低 IKK/NF-κB 激活的 Tax 突变减弱，并通过使用 I-κBα 的降解抗性突变体阻断 NF-κB 来防止，尽管 IKK 持续激活。小发夹 RNA 介导的敲低表明，RelA 通过作用于后期促进复合物上游并分别作用于 RelB 来稳定 p27（KIP1）蛋白和 p21（CIP1/WAF1）mRNA 来诱导该衰老程序。最后，我们表明 HTLV-1 反义蛋白 HBZ 下调 NF-κB 可延迟或防止 Tax 诱导的衰老发生。我们提出，Tax 和 HBZ 表达之间的平衡决定了 HTLV-1 感染的结果。强大的 HTLV-1 复制和 Tax 表达增加驱动 IKK/NF-κB 过度激活并引发衰老。然而，HBZ 调节 Tax 介导的病毒复制和 NF-κB 激活，从而允许 HTLV-1 感染的细胞增殖、持续存在并进化。最后，衰老检查点的失活可促进持续的 NF-κB 激活和白血病发生。
