The Absence of Caveolin-1 Increases Proliferation and Anchorage-Independent Growth by a Rac-Dependent, Erk-Independent Mechanism
The Absence of Caveolin-1 Increases Proliferation and Anchorage-Independent Growth by a Rac-Dependent, Erk-Independent Mechanism
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DOI：
10.1128/mcb.00315-09
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发表时间：
2009-09-15
影响因子：
5.3
通讯作者：
del Pozo, Miguel A.
中科院分区：
文献类型：
--
作者：
Cerezo, Ana;Guadamillas, Marta C.;del Pozo, Miguel A.
癌细胞的锚定非依赖性生长（AIG）需要逃避整合素介导的信号。一种在癌症中经常下调的蛋白质，小窝蛋白-1（Cav 1），介导几种生长调节途径的整合素控制。我们报告说，Cav 1的损失导致更快地退出静止和进展通过细胞周期，增殖无锚定基板，和缺乏细胞周期蛋白D1下调血清剥夺或脱离。令人惊讶的是，这种增殖优势是独立的ERK-丝裂原活化蛋白激酶信号转导，相反，细胞周期蛋白的表达和细胞周期的进展，在Cav 1的情况下，由增加膜秩序和Rac靶向驱动。通过Rac 1的强制膜靶向或通过抑制Rac 1积累的质膜有序结构域的Cav 1介导的内化，在Cav 1表达细胞中诱导AIG。恢复Rho的活性，这是下调后的Cav 1的损失，拮抗Rac 1和防止细胞周期蛋白D1积累后血清饥饿或粘附损失。因此，Cav 1缺陷型肿瘤细胞和空细胞中的锚定独立性和增殖增加是由于膜有序结构域中活性Rac 1的分数增加。这些结果提供了对调节癌细胞生长的机制的深入了解，这些癌细胞经常失去Cav 1功能。
Anchorage-independent growth (AIG) of cancer cells requires escape from integrin-mediated signals. A protein frequently downregulated in cancer, caveolin-1 (Cav1), mediates integrin control of several growth-regulatory pathways. We report that loss of Cav1 results in faster exit from quiescence and progress through the cell cycle, proliferation without anchorage to substrate, and absence of cyclin D1 downregulation upon serum deprivation or detachment. Surprisingly, this proliferative advantage is independent of Erk-mitogen-activated protein kinase signaling; instead, cyclin expression and cell cycle progression in the absence of Cav1 are driven by increased membrane order and Rac targeting. AIG was induced in Cav1-expressing cells by forced membrane targeting of Rac1 or by inhibiting Cav1-mediated internalization of plasma membrane ordered domains at which Rac1 accumulates. Restoring Rho activity, which is downregulated after loss of Cav1, antagonizes Rac1 and prevents cyclin D1 accumulation after serum starvation or loss of adhesion. Anchorage independence and increased proliferation in Cav1-deficient tumoral and null cells are thus due to an increased fraction of active Rac1 at membrane ordered domains. These results provide insight into the mechanisms regulating growth of cancer cells, which frequently lose Cav1 function.