Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization.
Cytoplasmic translocation of the retinoblastoma protein disrupts sarcomeric organization.
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作者：
Araki K;Kawauchi K;Hirata H;Yamamoto M;Taya Y
骨骼肌退化是包括晚期癌症在内的多种慢性疾病引起的并发症。促炎细胞因子 TNF-α 在介导癌症相关骨骼肌变性中发挥着关键作用。在这里，我们展示了视网膜母细胞瘤蛋白 (Rb) 的一种新功能，其中 Rb 会导致肌节紊乱。在人骨骼肌肌管 (HSMM) 中，TNF-α 处理诱导细胞周期蛋白依赖性激酶 4 (CDK4) 上调并伴随 Rb 磷酸化，导致磷酸化 Rb 易位至细胞质。此外，核输出信号（NES）融合形式的 Rb 的诱导表达导致肌节组织的破坏。我们鉴定出哺乳动物透明相关的 formin 1 (mDia1)（一种有效的肌动蛋白成核因子）作为细胞质 Rb 的结合伴侣，并发现 mDia1 有助于维持肌节的结构完整性。这些结果揭示了 Rb 的一种新的非核功能，并提出了 TNF-α 诱导肌节组织破坏的潜在机制。 DOI：http://dx.doi.org/10.7554/eLife.01228.001 骨骼肌，如二头肌和小腿，是人体三大主要肌肉群之一，一系列慢性疾病（包括癌症、心脏病和艾滋病）可能会导致这些肌肉消耗和力量丧失。已知许多不同的细胞过程与疾病期间骨骼肌的退化有关。例如，在患有癌症的人中，免疫反应会产生大量称为炎症细胞因子的分子来对抗癌细胞，这些分子被认为在骨骼肌的分解中发挥着作用。一种称为肿瘤坏死因子α（简称TNF-α）的细胞因子被认为会导致肌肉损伤，但这一过程的细节尚不完全清楚。一种可能性是 TNF-α 与一种名为 Rb（视网膜母细胞瘤蛋白的缩写）的蛋白质相互作用，该蛋白质可抑制导致癌症的细胞增殖。然而，如果这种蛋白质通过磷酸化化学过程进行修饰，Rb 分子将无法抑制导致细胞过度生长的基因。在许多癌细胞中都观察到了 Rb 的过度磷酸化，并且已经表明细胞中高水平的 TNF-α 会导致 Rb 无法正常工作，但尚不清楚错误的 Rb 是否也会导致骨骼肌的损坏。现在荒木等人。提供证据表明 TNF-α 磷酸化 Rb 会导致骨骼肌变性。荒木等人。发现在含有高浓度 TNF-α 的肌肉细胞中，Rb 分子从细胞核移动到细胞质，在那里它们与基因相互作用，并在那里破坏结构纤维的形成。这意味着铷会抑制肌肉细胞在收缩和放松过程中滑动的能力，就像正常肌肉组织中发生的那样。如果通过进一步的实验得到证实，这些结果可能会导致开发治疗骨骼肌退化的新方法。 DOI：http://dx.doi.org/10.7554/eLife.01228.002
Skeletal muscle degeneration is a complication arising from a variety of chronic diseases including advanced cancer. Pro-inflammatory cytokine TNF-α plays a pivotal role in mediating cancer-related skeletal muscle degeneration. Here, we show a novel function for retinoblastoma protein (Rb), where Rb causes sarcomeric disorganization. In human skeletal muscle myotubes (HSMMs), up-regulation of cyclin-dependent kinase 4 (CDK4) and concomitant phosphorylation of Rb was induced by TNF-α treatment, resulting in the translocation of phosphorylated Rb to the cytoplasm. Moreover, induced expression of the nuclear exporting signal (NES)-fused form of Rb caused disruption of sarcomeric organization. We identified mammalian diaphanous-related formin 1 (mDia1), a potent actin nucleation factor, as a binding partner of cytoplasmic Rb and found that mDia1 helps maintain the structural integrity of the sarcomere. These results reveal a novel non-nuclear function for Rb and suggest a potential mechanism of TNF-α-induced disruption of sarcomeric organization. DOI: http://dx.doi.org/10.7554/eLife.01228.001 Skeletal muscles, such as the biceps and calves, are one of three main muscle groups in the body, and a range of chronic diseases—including cancer, heart disease and AIDS—can cause wasting and a loss of strength in these muscles. Many different cellular processes are known to be involved in the degeneration of skeletal muscle during illness. For example, in people suffering from cancer, the immune response produces large numbers of molecules called inflammatory cytokines to combat the cancer cells, and these molecules are thought to have a role in the breakdown of skeletal muscle. A cytokine called tumour necrosis factor alpha, or TNF-α for short, is thought to cause muscle damage, but the details of this process are not fully understood. One possibility is that TNF-α interacts with a protein called Rb—short for retinoblastoma protein—that suppresses the proliferation of cells that leads to cancer. However, if this protein is modified by a chemical process called phosphorylation, the Rb molecules will not be able to suppress the genes that lead to excessive cell growth. The hyperphosphorylation of Rb has been observed in many cancer cells, and it has been shown that high levels of TNF-α in cells results in Rb not working properly, but it has not been clear if faulty Rb also leads to the breakdown of skeletal muscle. Now Araki et al. provide evidence that the phosphorylation of Rb by TNF-α leads to skeletal muscle degeneration. Araki et al. found that in muscle cells that contain high concentrations of TNF-α, the Rb molecules move from the nuclei of the cells, where they interact with genes, to the cytoplasm, where they disrupt the formation of structural fibres. This means that Rb inhibits the ability of muscle cells to slide over one during contractions and relaxation, as happens in normal muscle tissue. If confirmed by further experiments, these results could lead to the development of new approaches for the treatment of skeletal muscle degeneration. DOI: http://dx.doi.org/10.7554/eLife.01228.002