Benaud C M, Dickson R B
Vincent T Lombardi Cancer Center, Georgetown University Medical Center, 3970 Reservoir Rd. NW, Washington, DC 20007, USA.
Oncogene. 2001 Feb 8;20(6):759-68. doi: 10.1038/sj.onc.1204152.
Cell adhesion promotes cellular proliferation through the regulation of gene expression, including the immediate early genes. However, the precise role of cell adhesion in the regulation of the c-Myc proto-oncogene is not clear, and the adhesion-dependent signaling pathway(s) regulating the expression of c-Myc has yet to be defined. We now show that integrin signaling directly regulates the expression of c-Myc in the mammary epithelial cell line 184A1N4 (A1N4). Adhesion of quiescent A1N4 cells to fibronectin, and to collagen types IV or I, induces the expression of c-Myc in an ECM concentration-dependent fashion. Cytoskeletal rearrangement, and integrin engagement and integrin clustering are required for the induction of c-Myc by fibronectin. Furthermore, beta1 integrin function-blocking antibodies prevent the adhesion-dependent induction of c-Myc. Adhesion of A1N4 cells results in the activation both of c-Src and of the Erk 1/2 mitogen-activated protein kinase (MAPK), each of which precedes the induction of c-Myc. Pharmacological inhibitors specific for either the c-Src family of kinases or for MEK1 block the adhesion-dependent induction of c-Myc. These observations indicate that beta1 integrins regulate the expression of c-Myc through the activation of the Src family of tyrosine kinases and the MAK kinase pathway.
细胞黏附通过调控基因表达促进细胞增殖，其中包括即刻早期基因。然而，细胞黏附在c-Myc原癌基因调控中的精确作用尚不清楚，且调节c-Myc表达的黏附依赖性信号通路尚未明确。我们现在表明，整合素信号直接调控乳腺上皮细胞系184A1N4（A1N4）中c-Myc的表达。静止的A1N4细胞与纤连蛋白、IV型或I型胶原的黏附，以细胞外基质（ECM）浓度依赖性方式诱导c-Myc的表达。纤连蛋白诱导c-Myc表达需要细胞骨架重排、整合素结合及整合素聚集。此外，β1整合素功能阻断抗体可阻止c-Myc的黏附依赖性诱导。A1N4细胞的黏附导致c-Src和Erk 1/2丝裂原活化蛋白激酶（MAPK）的激活，二者均先于c-Myc的诱导。对c-Src激酶家族或MEK1具有特异性的药理学抑制剂可阻断c-Myc的黏附依赖性诱导。这些观察结果表明，β1整合素通过激活酪氨酸激酶Src家族和MAP激酶途径来调节c-Myc的表达。
