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首页> 外文期刊>Oncogene >The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation
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The HTLV-I Tax oncoprotein targets the retinoblastoma protein for proteasomal degradation

机译：HTLV-I Tax癌蛋白靶向视网膜母细胞瘤蛋白进行蛋白酶体降解

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Human T-cell leukemia virus type-I (HTLV-I), the etiologic agent of adult T-cell leukemia (ATL), is estimated to affect 10–20 million people worldwide. The transforming ability of HTLV-I has been largely attributed to the viral protein Tax, which modulates the activity of several well-known cell cycle regulators. An important cell cycle regulator, the retinoblastoma (Rb) protein, is often inactivated in many cancers including virally induced cancers. Upon examination of Rb status, we observed a decrease in Rb protein expression in HTLV-1-infected cell lines as well as in ex vivo ATL patient samples. Transient transfection assays indicated that decreased Rb protein levels were Tax dependent. Here, we demonstrate for the first time that Tax directly associates with Rb. This interaction was localized within the B pocket of Rb and the C-terminus of Tax (aa 245–353). Within the C-terminus of Tax, we have identified an LXCXE-like motif, that when mutated resulted in the loss of Tax/Rb interaction. Furthermore, through the use of proteasome inhibitors, such as MG-132, in vivo and proteasome degradation assays in vitro, we found that Tax destabilizes the hypo-phosphorylated (active) form of Rb via the proteasome pathway. Therefore, we propose a model whereby Tax targets Rb to the proteasome by acting as a molecular bridge bringing Rb into contact with the proteasome for degradation.
机译：I型人类T细胞白血病病毒（HTLV-1）是成人T细胞白血病（ATL）的病原体，估计会影响全球10至2000万人。 HTLV-1的转化能力很大程度上归因于病毒蛋白Tax，它调节了几种众所周知的细胞周期调节剂的活性。一个重要的细胞周期调节剂，成视网膜细胞瘤（Rb）蛋白，经常在许多癌症（包括病毒诱发的癌症）中失活。在检查Rb状态后，我们观察到HTLV-1感染的细胞系以及离体ATL患者样品中Rb蛋白表达的下降。瞬时转染分析表明，Rb蛋白水平降低与Tax相关。在这里，我们首次证明Tax直接与Rb相关联。这种相互作用位于Rb的B口袋和Tax的C端（aa 245-353）内。在Tax的C末端，我们确定了一个LXCXE样的基序，该基序在突变时会导致Tax / Rb相互作用的丧失。此外，通过使用蛋白酶体抑制剂（例如MG-132），体内和体外蛋白酶体降解试验，我们发现Tax通过蛋白酶体途径使Rb的次磷酸化（活性）形式不稳定。因此，我们提出了一个模型，其中Tax通过充当使Rb与蛋白酶体接触降解的分子桥，将Rb靶向蛋白酶体。

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