Crouch D H, Fincham V J, Frame M C
The Beatson Institute for Cancer Research, Cancer Research Campaign Beatson Laboratories, Glascow, UK.
Oncogene. 1996 Jun 20;12(12):2689-96.
The product of the c-myc proto-oncogene has a central role in induction of apoptosis, a physiological form of cell death characterised in vitro by morphological rounding, detachment and nuclear disintegration. Induction of apoptosis by serum withdrawal from c-Myc-transformed chicken embryo fibroblasts (CEF) results in early proteolysis of focal adhesion kinase (ppl25FAK), a tyrosine kinase implicated in the conversion of integrin signals into their biological responses. Proteolysis of pp125 FAK occurs in adherent cells prior to commitment to death, suggesting that it contributes to c-Myc-induced apoptosis, rather than being a consequence of it. Furthermore, c-Myc-induced detachment, cell death and cleavage of pp125FAK are coordinately suppressed by treating with insulin or plating on the extracellular matrix components collagen and fibronectin. In addition, proteolysis of pp125FAK is suppressed by a beta1-specific integrin antibody, which promotes cell survival in the face of the oncoprotein-induced signal for apoptosis. These results provide compelling evidence that the c-Myc-induced cell death programme in CEF requires disruption of the integrin signalling pathways which normally function when cells are spread on ECM, and that maintaining cellular pp125FAK, which couples integrins to their downstream effectors, is closely linked to cell survival.
原癌基因c-myc的产物在细胞凋亡诱导过程中起核心作用，细胞凋亡是一种生理性细胞死亡形式，在体外其特征为形态变圆、脱离和核解体。从c-Myc转化的鸡胚成纤维细胞（CEF）中撤除血清诱导细胞凋亡，会导致粘着斑激酶（pp125FAK）早期蛋白水解，粘着斑激酶是一种酪氨酸激酶，参与将整合素信号转化为其生物学反应。pp125 FAK的蛋白水解发生在贴壁细胞死亡之前，这表明它有助于c-Myc诱导的细胞凋亡，而不是细胞凋亡的结果。此外，通过用胰岛素处理或接种在细胞外基质成分胶原蛋白和纤连蛋白上，可协同抑制c-Myc诱导的脱离、细胞死亡和pp125FAK的裂解。另外，一种β1特异性整合素抗体可抑制pp125FAK的蛋白水解，该抗体在面对癌蛋白诱导的细胞凋亡信号时可促进细胞存活。这些结果提供了令人信服的证据，即CEF中c-Myc诱导的细胞死亡程序需要破坏整合素信号通路，而整合素信号通路在细胞铺展于细胞外基质时通常发挥作用，并且维持将整合素与其下游效应器偶联的细胞pp125FAK与细胞存活密切相关。
