Pasteurella multocida toxin is a potent activator of anti‐apoptotic signalling pathways-猫眼课题宝

多杀性巴氏杆菌毒素是抗凋亡信号通路的有效激活剂

DOI：

发表时间：

2010

期刊：

Cellular Microbiology

影响因子：

3.4

通讯作者：

中科院分区：

生物学2区

文献类型：

作者：

I. Preuss;D. Hildebrand;Joachim H. C. Orth;K. Aktories;K. Kubatzky

产毒素多杀性巴氏杆菌菌株产生146 kDa蛋白毒素（PMT），由于其高促有丝分裂活性，被认为具有致癌特性。 PMT通过组成性刺激异源三聚体G蛋白影响与癌症相关的几个信号转导途径。在Gαq、Gα13和Gαi的下游，该毒素激活小G蛋白RhoA、MAP激酶以及信号转导和转录激活因子（STAT）蛋白。PMT还刺激Gβγ信号传导并激活磷酸肌醇3激酶（PI 3 K）相关通路，这在增殖和凋亡中起着至关重要的作用。我们发现用PMT处理HEK 293细胞通过Akt的PI 3 K依赖性磷酸化和Pim-1激酶的组成性表达抑制星形孢菌素介导的凋亡。这些存活激酶的同时激活允许激活促存活途径，如GSK 3 β、Mcl-1、Bcl-xL和Bcl-2，以及Bax或Puma下调凋亡信号。只有Akt和Pim的联合抑制逆转了PMT诱导的对星形孢菌素诱导的细胞凋亡的保护。此外，我们表明，肿瘤化疗药物诱导的细胞凋亡被PMT在人类癌细胞系中阻断。我们的数据表明，PMT是一种高效的抗凋亡剂，这支持了毒素致癌潜力的观点。

Toxigenic Pasteurella multocida strains produce a 146 kDa protein toxin (PMT) that due to its high mitogenic activity is thought to possess carcinogenic properties. PMT affects several signal transduction pathways related to cancer by constitutively stimulating heterotrimeric G proteins. Downstream of Gαq, Gα13 and Gαi, the toxin activates the small GTPase RhoA, MAP kinases and signal transducer and activator of transcription (STAT) proteins. PMT also stimulates Gβγ signalling and activates phosphoinositide 3‐kinase (PI3K)‐related pathways, which play a crucial role in proliferation and apoptosis. We show that treatment of HEK293 cells with PMT inhibits staurosporine‐mediated apoptosis through PI3K‐dependent phosphorylation of Akt and constitutive expression of Pim‐1 kinase. Simultaneous activation of these survival kinases allows the activation of pro‐survival pathways, such as GSK3β, Mcl‐1, Bcl‐xL and Bcl‐2, as well as the downregulation of apoptotic signals by Bax or Puma. Only the combined inhibition of Akt and Pim reverses the PMT‐induced protection from staurosporine‐induced apoptosis. In addition, we show that apoptosis induced by tumour chemotherapeutic agents is blocked by PMT in human cancer cell lines. Our data indicate that PMT is a highly potent anti‐apoptotic agent, which supports the view of a carcinogenic potential of the toxin.