Daly J M, Olayioye M A, Wong A M, Neve R, Lane H A, Maurer F G, Hynes N E
Friedrich Miescher Institute, Basel, Switzerland.
Oncogene. 1999 Jun 10;18(23):3440-51. doi: 10.1038/sj.onc.1202700.
Neu differentiation factor (NDF)/heregulin activates ErbB2 via heterodimerization with the NDF receptors ErbB3 and ErbB4. Cells which express normal levels of these receptors are often growth stimulated by NDF, whereas SKBR3, and other ErbB2-overexpressing breast tumour cells are growth inhibited. We demonstrate here that in SKBR3 cells, NDF induces G1 progression but also causes a G2 delay from day 1 and apoptosis from days 2-3. G1 progression was associated with ErbB2 transactivation of ErbB3 and subsequent stimulation of the phosphatidylinositol 3-kinase (PI3K) pathway whereas apoptosis was dependent on p38 MAPK. Inhibition of ERK1/ERK2 had no effect on cell cycle progression or apoptosis. Activation of ErbB3 and PI3K was also seen with betacellulin (BTC) but not epidermal growth factor (EGF) and correlated with the growth effects of these ligands. All three ligands induced short-term activation of p38 MAPK in a c-Src-dependent manner. However, only NDF caused a second, c-Src-independent increase in p38 MAPK activity which was required for apoptosis.
神经分化因子（NDF）/ 神经调节蛋白通过与NDF受体ErbB3和ErbB4异源二聚化来激活ErbB2。表达这些受体正常水平的细胞通常会被NDF刺激生长，而SKBR3细胞以及其他过表达ErbB2的乳腺肿瘤细胞则生长受抑制。我们在此证明，在SKBR3细胞中，NDF诱导G1期进程，但也会从第1天开始导致G2期延迟，并从第2 - 3天开始引发细胞凋亡。G1期进程与ErbB2对ErbB3的反式激活以及随后对磷脂酰肌醇3激酶（PI3K）途径的刺激有关，而细胞凋亡则依赖于p38丝裂原活化蛋白激酶（MAPK）。抑制细胞外信号调节激酶1/2（ERK1/ERK2）对细胞周期进程或细胞凋亡没有影响。β细胞素（BTC）也能激活ErbB3和PI3K，但表皮生长因子（EGF）不能，且这与这些配体的生长效应相关。所有三种配体均以c - Src依赖的方式诱导p38 MAPK的短期激活。然而，只有NDF会导致p38 MAPK活性出现第二次、不依赖c - Src的增加，而这是细胞凋亡所必需的。
