Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis.
Rho-associated kinase (ROCK) function is essential for cell cycle progression, senescence and tumorigenesis.
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DOI：
10.7554/elife.12203
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发表时间：
2016-01-14
期刊：
影响因子：
7.7
通讯作者：
Marshall CJ
中科院分区：
文献类型：
--
作者：
Kümper S;Mardakheh FK;McCarthy A;Yeo M;Stamp GW;Paul A;Worboys J;Sadok A;Jørgensen C;Guichard S;Marshall CJ
Rho相关激酶1和2（ROCK 1/2）是Rho-GTdR效应子，其控制肌动蛋白细胞骨架的关键方面，但其在增殖和癌症起始或进展中的作用尚不清楚。在这里，我们提供的证据表明，ROCK 1和ROCK 2的行为冗余，以维持肌动球蛋白的收缩性和细胞增殖，他们的损失导致细胞周期停滞和细胞衰老。这种表型是由细胞周期蛋白CyclinA、CKS 1和CDK 1的下调引起的。因此，虽然Rock 1或Rock 2的缺失对非小细胞肺癌和黑色素瘤小鼠模型中的肿瘤发生没有负面影响，但两者的缺失阻断了肿瘤形成，因为其中Rock 1和Rock 2都已被基因删除的肿瘤不会出现。我们的研究结果揭示了ROCK在细胞周期进展和肿瘤发生中的不可或缺的作用，但亚型1和2的作用是多余的，可能是通过维持细胞的收缩性。http://dx.doi.org/10.7554/eLife.12203.001动物细胞含有一种称为细胞骨架的结构，它有助于赋予细胞形状。这种结构可以快速分解和重新组装，使细胞能够改变形状，移动和分裂成两个。许多蛋白质参与控制这些过程。特别是，已知两种称为ROCK 1和ROCK 2的蛋白质对帮助癌细胞移动很重要。然而，对这些蛋白质的确切作用的研究迄今为止产生了相互矛盾的结果。Kümper等人现在已经开发出一种更精确的方法来研究ROCK 1和ROCK 2在细胞中的作用。这涉及到基因工程小鼠的方式，使其有可能控制ROCK 1和ROCK 2是否在特定的细胞类型和组织中产生。研究从这些小鼠身上提取的细胞发现，缺乏这两种蛋白质的细胞不能收缩。此外，这些细胞变得更大，更扁平。这种外观上的变化与细胞无法分裂和形成新细胞密切相关。然而，缺乏一种ROCK蛋白的细胞仍然能够分裂和增殖。由于肿瘤是由于细胞不受控制地分裂和增殖而形成的，Kümper等人随后研究了ROCK蛋白如何影响易患肺癌或皮肤癌的小鼠的肿瘤发展。虽然发现癌细胞仅含有一种类型的ROCK蛋白，但没有发现缺乏ROCK 1和ROCK 2的肿瘤细胞，进一步证实了具有一种ROCK蛋白对于肿瘤形成是必需的。总的来说，在研究的系统中，ROCK 1和ROCK 2似乎起着相同的作用，并且ROCK蛋白对于细胞增殖和肿瘤发展是不可或缺的。下一个挑战将是识别高度依赖于ROCK蛋白驱动的过程的肿瘤类型。进一步的工作可以研究抑制ROCK蛋白活性的药物是否会阻止这些肿瘤的生长和扩散。DOI：http://dx.doi.org/10.7554/eLife.12203.002网站
Rho-associated kinases 1 and 2 (ROCK1/2) are Rho-GTPase effectors that control key aspects of the actin cytoskeleton, but their role in proliferation and cancer initiation or progression is not known. Here, we provide evidence that ROCK1 and ROCK2 act redundantly to maintain actomyosin contractility and cell proliferation and that their loss leads to cell-cycle arrest and cellular senescence. This phenotype arises from down-regulation of the essential cell-cycle proteins CyclinA, CKS1 and CDK1. Accordingly, while the loss of either Rock1 or Rock2 had no negative impact on tumorigenesis in mouse models of non-small cell lung cancer and melanoma, loss of both blocked tumor formation, as no tumors arise in which both Rock1 and Rock2 have been genetically deleted. Our results reveal an indispensable role for ROCK, yet redundant role for isoforms 1 and 2, in cell cycle progression and tumorigenesis, possibly through the maintenance of cellular contractility. DOI: http://dx.doi.org/10.7554/eLife.12203.001 Animal cells contain a structure called the cytoskeleton, which helps give the cells their shape. This structure can rapidly disassemble and reassemble, which enables cells to change their shape, move and divide into two. Many proteins are involved in controlling these processes. In particular, two proteins called ROCK1 and ROCK2 are known to be important for helping cancer cells move. However, investigations into the exact roles of these proteins have so far produced contradictory results. Kümper et al. have now developed a more refined method of studying what ROCK1 and ROCK2 do in cells. This involves genetically engineering mice in a way that makes it possible to control whether ROCK1 and ROCK2 are produced in specific cell types and tissues. Studying cells that had been taken from these mice revealed that cells that lacked both proteins could not contract. Moreover, these cells became bigger and flattened out. This change in appearance went hand in hand with the cells becoming unable to divide and form new cells. However, cells that lacked just one type of ROCK protein were still able to divide and proliferate. As tumors form as a result of cells dividing and proliferating uncontrollably, Kümper et al. then studied how the ROCK proteins affect tumor development in mice that are susceptible to lung or skin cancer. Although cancerous cells were found that contained just one type of ROCK protein, no tumor cells were found that lacked both ROCK1 and ROCK2, further confirming that having one ROCK protein is essential for tumor formation. Overall, it appears that within the systems studied ROCK1 and ROCK2 perform the same roles, and that ROCK proteins are indispensable for cell proliferation and hence tumor development. The next challenge will be to identify the tumor types that are highly dependent on processes driven by the ROCK proteins. Further work could then investigate whether drugs that inhibit the activity of the ROCK proteins block the growth and spread of these tumors. DOI: http://dx.doi.org/10.7554/eLife.12203.002