Trevisan Roberta, Daprai Laura, Paloschi Lucia, Vajente Nicola, Chieco-Bianchi Luigi, Saggioro Daniela
Department of Oncology and Surgical Sciences, Oncology Section, University of Padova, Italy.
Exp Cell Res. 2006 May 1;312(8):1390-400. doi: 10.1016/j.yexcr.2006.01.009. Epub 2006 Feb 17.
Defects in the regulation of programmed cell death play a fundamental role in the development of neoplasia and neurological disorders, both of which are linked to the human T-cell leukemia/lymphoma virus type 1 (HTLV-1) infection. We previously showed that the HTLV-1 Tax protein protects from apoptosis induced by serum starvation by preventing cytochrome c release and Bax relocation to mitochondria, two early events in the mitochondrial apoptotic pathway. As a natural extension of these findings, and to better define the action of Tax, in the present study, we investigated the outcome of Tax and two mutants which are inactive in CREB/ATF (M47) or NF-kappaB (M22) pathways, in the control of apoptosis induced by the proapoptotic Bax protein. We found that activation of CREB, rather than NF-kappaB, is a key phenomenon in preventing apoptosis. Furthermore, the importance of CREB activation is strengthened by experiments with CREB mutants, treatment with forskolin, and in situ analysis of P-CREB status in cells transfected with Tax or its nonprotecting M47 mutant. Considered together, these results underscore a primary role of CREB in preventing apoptosis triggered by Bax, and suggest that Tax might act by affecting the phosphorylation state of CREB.
程序性细胞死亡调控缺陷在肿瘤形成和神经疾病发展过程中发挥着重要作用，这两种情况均与人类1型T细胞白血病/淋巴瘤病毒（HTLV-1）感染有关。我们之前发现，HTLV-1 Tax蛋白通过阻止细胞色素c释放以及Bax转位至线粒体（这是线粒体凋亡途径中的两个早期事件），从而保护细胞免受血清饥饿诱导的凋亡。作为这些发现的自然延伸，并且为了更好地界定Tax的作用，在本研究中，我们研究了Tax以及在CREB/ATF（M47）或NF-κB（M22）途径中无活性的两个突变体在调控促凋亡Bax蛋白诱导的凋亡中的结果。我们发现，CREB的激活而非NF-κB的激活是预防凋亡的关键现象。此外，通过使用CREB突变体进行实验、用福司可林处理以及对转染了Tax或其无保护作用的M47突变体的细胞中的磷酸化CREB状态进行原位分析，进一步强化了CREB激活的重要性。综合考虑，这些结果强调了CREB在预防由Bax触发的凋亡中的主要作用，并表明Tax可能通过影响CREB的磷酸化状态发挥作用。
