Atfi A, Buisine M, Mazars A, Gespach C
INSERM U 55 and IFR 65 (Institut Fédératif de Recherche du Centre Hospitalo-Universitaire Saint-Antoine), Hôpital Saint-Antoine, 184 Rue du Faubourg Saint-Antoine, 75571, Paris Cedex 12, France.
J Biol Chem. 1997 Oct 3;272(40):24731-4. doi: 10.1074/jbc.272.40.24731.
Many of the actions of serine/threonine kinase receptors for the transforming growth factor-beta (TGFbeta) are mediated by DPC4, a human MAD-related protein identified as a tumor suppressor gene in pancreatic carcinoma. Overexpression of DPC4 is sufficient to induce the activation of gene expression and cell cycle arrest, characteristic of the TGFbeta response. The stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) is also one of the downstream targets required for TGFbeta-mediated signaling. Here we report that expression of the dominant-interfering mutant of various components of the SAPK/JNK cascade specifically blocked both TGFbeta and DPC4-induced gene expression. These dominant-interfering mutants also inhibited TGFbeta-stimulated DPC4 transcriptional activity. Moreover, we find that overexpression of DPC4 causes transfected cells to undergo the morphological changes typical of apoptosis. These findings define a mechanism whereby TGFbeta signals mediated by DPC4 and SAPK/JNK cascade are integrated in the nucleus to activate gene expression and identify a new cellular function for DPC4.
转化生长因子-β（TGFβ）的丝氨酸/苏氨酸激酶受体的许多作用是由DPC4介导的，DPC4是一种人类MAD相关蛋白，在胰腺癌中被鉴定为肿瘤抑制基因。DPC4的过表达足以诱导基因表达的激活和细胞周期停滞，这是TGFβ反应的特征。应激激活蛋白激酶/c-Jun氨基末端激酶（SAPK/JNK）也是TGFβ介导的信号传导所需的下游靶点之一。在此，我们报告，SAPK/JNK级联反应的各种组分的显性干扰突变体的表达特异性地阻断了TGFβ和DPC4诱导的基因表达。这些显性干扰突变体也抑制了TGFβ刺激的DPC4转录活性。此外，我们发现DPC4的过表达导致转染细胞发生典型的凋亡形态变化。这些发现确定了一种机制，通过该机制，由DPC4和SAPK/JNK级联反应介导的TGFβ信号在细胞核中整合以激活基因表达，并确定了DPC4的一种新的细胞功能。
