Integrated Systems and Technologies : Mathematical Oncology p 38 g Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase , Cytoskeletal Architecture , and a Novel Leading Edge Behavior
Integrated Systems and Technologies : Mathematical Oncology p 38 g Promotes Breast Cancer Cell Motility and Metastasis through Regulation of RhoC GTPase , Cytoskeletal Architecture , and a Novel Leading Edge Behavior
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发表时间：
2011
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通讯作者：
D. Rosenthal;H. Iyer;Silvia Escudero;Liwei Bao;Zhi-fen Wu;A. Ventura;C. Kleer;E. Arruda;K. Garikipati;S. Merajver
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作者：
D. Rosenthal;H. Iyer;Silvia Escudero;Liwei Bao;Zhi-fen Wu;A. Ventura;C. Kleer;E. Arruda;K. Garikipati;S. Merajver
了解赋予癌细胞能动性和转移性的分子改变是提高患者生存率所必需的。在这里，我们报告说，p38 g运动原激活蛋白激酶调节乳腺癌细胞的运动和转移，部分，通过控制表达的转移相关的小GTdR RhoC。这种p38 g-RhoC调控连接是由一种新的调节RhoC泛素化的机制介导的。这种关系在多个细胞系和临床乳腺癌标本中持续存在。使用基于有限元方法的计算力学模型，我们表明，p38 g介导的细胞骨架的变化足以控制细胞运动。该模型预测了肌动蛋白前缘突起的新动力学，并通过实验验证了其与细胞形状和细胞骨架形态密切相关。p38 g表达升高与乳腺癌患者总体生存率降低相关的证据支持了临床相关性。总之，我们的结果提供了p38 g如何促进乳腺癌进展的详细特征。在这里，我们提出了一个新的力学为基础的分析细胞运动，并报告发现的前沿行为，在运动细胞，以适应修改后的细胞骨架结构。总之，这些发现不仅确定了一种新的机制，调节RhoC的表达，但也推进p38 g作为一个候选的治疗靶点。Cancer Res; 71（20）; 6338-49. 2011年AACR。
Understanding the molecular alterations that confer cancer cells with motile, metastatic properties is needed to improve patient survival. Here, we report that p38g motogen-activated protein kinase regulates breast cancer cell motility and metastasis, in part, by controlling expression of the metastasis-associated small GTPase RhoC. This p38g–RhoC regulatory connection wasmediated by a novel mechanism of modulating RhoC ubiquitination. This relationship persisted across multiple cell lines and in clinical breast cancer specimens. Using a computational mechanical model based on the finite element method, we showed that p38g-mediated cytoskeletal changes are sufficient to control cell motility. This model predicted novel dynamics of leading edge actin protrusions, whichwere experimentally verified and established to be closely related to cell shape and cytoskeletal morphology. Clinical relevance was supported by evidence that elevated expression of p38g is associated with lower overall survival of patientswithbreast cancer. Taken together, our results offer a detailed characterizationof how p38g contributes to breast cancer progression. Herein we present a new mechanics-based analysis of cell motility, and report on the discovery of a leading edge behavior in motile cells to accommodate modified cytoskeletal architecture. In summary, these findings not only identify a novel mechanism for regulating RhoC expression but also advance p38g as a candidate therapeutic target. Cancer Res; 71(20); 6338–49. 2011 AACR.