Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Campus de Cantoblanco, 28049 Madrid, Spain.
Carcinogenesis. 2011 Jul;32(7):1093-9. doi: 10.1093/carcin/bgr079. Epub 2011 May 10.
The p38 mitogen-activated protein kinase (p38MAPK) signal transduction pathway is an important regulator of cell processes, whose deregulation leads to the development and progression of cancer. Defining the role of each p38MAPK family member in these processes has been difficult. To date, most studies of the p38MAPK pathways focused on function of the p38α isoform, which is widely considered to negatively regulate malignant transformation; nonetheless, few reports address the p38γ and p38δ isoforms. Here, we used embryonic fibroblasts derived from mice lacking p38γ or p38δ and show evidence that these isoforms participate in several processes involved in malignant transformation. We observed that lack of either p38γ or p38δ increased cell migration and metalloproteinase-2 secretion, whereas only p38δ deficiency impaired cell contact inhibition. In addition, lack of p38γ in K-Ras-transformed fibroblasts led to increased cell proliferation as well as tumorigenesis both in vitro and in vivo. Our results indicate that p38γ and p38δ have a role in the suppression of tumor development.
p38 丝裂原活化蛋白激酶（p38MAPK）信号转导通路是细胞过程的重要调节剂，其失调会导致癌症的发生和发展。定义 p38MAPK 家族每个成员在这些过程中的作用一直具有挑战性。迄今为止，大多数 p38MAPK 通路的研究都集中在 p38α 同工型的功能上，p38α 被广泛认为可负调控恶性转化；然而，很少有报道涉及 p38γ 和 p38δ 同工型。在这里，我们使用缺乏 p38γ 或 p38δ 的小鼠胚胎成纤维细胞，证明这些同工型参与了恶性转化涉及的几个过程。我们观察到，缺乏 p38γ 或 p38δ 均可增加细胞迁移和金属蛋白酶-2 的分泌，而只有 p38δ 缺乏会损害细胞接触抑制。此外，缺乏 p38γ 的 K-Ras 转化成纤维细胞会导致体外和体内细胞增殖增加以及肿瘤发生。我们的结果表明，p38γ 和 p38δ 在抑制肿瘤发展中具有作用。
