Solovyan Victor T, Keski-Oja Jorma
Department of Pathology, Haartman Institute, University of Helsinki, Biomedicum Helsinki and Helsinki University Hospital, Helsinki, Finland.
J Cell Physiol. 2006 May;207(2):445-53. doi: 10.1002/jcp.20607.
Transforming growth factors beta (TGF-betas) are multifunctional cytokines, which are secreted in latent forms in large latent TGF-beta complexes (LL-TGF-beta) with subsequent deposition to the extracellular matrix (ECM). While a variety of mechanisms capable of activating latent TGF-beta in vitro have been described, the physiological conditions, which promote the activation of TGF-beta in vivo are poorly understood. Mink lung epithelial cells (Mv1Lu) are a widely used model for evaluation of the effects of exogenous TGF-beta both in transcriptional and growth inhibitor assays. We find here that apoptosis of Mv1Lu cells, induced either by staurosporine or serum deprivation, is accompanied by proteolytic processing of LL-TGF-beta and the activation of endogenous TGF-beta. Activation of TGF-beta preceded caspase-3 activation and was almost completely suppressed by the serine protease inhibitor, AEBSF. Both exogenous and endogenously activated TGF-betas were able to enhance the apoptotic response of Mv1Lu cells leading to potentiation of cell death. Potentiation of cell death by activated TGF-beta was associated with downregulation of Akt and p38 MAPK, which were both activated at the initial stages of Mv1Lu apoptosis and were suppressed by exogenous TGF-beta. Pharmacological interruption of either phosphoinositide-3-kinase (PI-3K)/Akt or p38 MAPK signaling by the specific inhibitors mimicked the effect of TGF-beta leading to potentiation of cell death. Current results suggest that proteolytic activation of endogenous TGF-beta is a component of the apoptotic response, capable of modulating the death of Mv1Lu cells by inhibition of both PI-3K/Akt and p38 MAPK-dependent survival pathways.
转化生长因子β（TGF-βs）是多功能细胞因子，以潜伏形式分泌于大型潜伏TGF-β复合物（LL-TGF-β）中，随后沉积到细胞外基质（ECM）。虽然已经描述了多种能够在体外激活潜伏TGF-β的机制，但对体内促进TGF-β激活的生理条件却知之甚少。貂肺上皮细胞（Mv1Lu）是一种广泛用于评估外源性TGF-β在转录和生长抑制试验中作用的模型。我们在此发现，由星形孢菌素或血清剥夺诱导的Mv1Lu细胞凋亡，伴随着LL-TGF-β的蛋白水解加工和内源性TGF-β的激活。TGF-β的激活先于caspase-3的激活，并且几乎完全被丝氨酸蛋白酶抑制剂AEBSF抑制。外源性和内源性激活的TGF-βs均能够增强Mv1Lu细胞的凋亡反应，导致细胞死亡的增强。激活的TGF-β增强细胞死亡与Akt和p38 MAPK的下调有关，这两者在Mv1Lu细胞凋亡的初始阶段被激活，并被外源性TGF-β抑制。特异性抑制剂对磷酸肌醇-3-激酶（PI-3K）/Akt或p38 MAPK信号的药理学阻断模拟了TGF-β的作用，导致细胞死亡增强。目前结果表明内源性TGF-β的蛋白水解激活是凋亡反应的一个组成部分，能够通过抑制PI-3K/Akt和p38 MAPK依赖的存活途径来调节Mv1Lu细胞的死亡。
