Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis
Proto-oncogene, Pim-3 with serine/threonine kinase activity, is aberrantly expressed in human colon cancer cells and can prevent Bad-mediated apoptosis
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DOI：
10.1111/j.1349-7006.2007.00390.x
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发表时间：
2007-03-01
期刊：
影响因子：
5.7
通讯作者：
Mukaida, Naofumi
中科院分区：
文献类型：
--
作者：
Popivanova, Boryana Konstantinova;Li, Ying-Yi;Mukaida, Naofumi
我们先前观察到具有丝氨酸/苏氨酸激酶活性的Pim-3在内胚层来源的器官、肝脏和胰腺的恶性病变中异常表达。由于Pim-3蛋白在正常结肠粘膜组织中未检测到，因此我们评估了Pim-3在另一种内胚层来源器官人类结肠的恶性病变中的表达。Pim-3在高分化腺癌（43/68例）和中分化腺癌（23/41例）中表达阳性，而在低分化腺癌（0/5例）中无表达。Pim-3蛋白在腺瘤（35/40例）和癌旁正常粘膜（26/111例）中均有表达。Pim-3在SW 480细胞中呈组成性表达，转染Pim-3短发夹RNA可促进SW 480细胞凋亡。在同一细胞系中，促凋亡分子Bad在代表其失活形式的Ser（112）和Ser（136）磷酸化位点处被磷酸化。Pim-3敲低可消除该细胞系中的Ser（112）磷酸化，但不消除Ser（136）磷酸化。此外，在人结肠癌组织中，Pim-3在所有情况下（9/9）与Bad共定位，并且在大多数情况下（6/9）与磷酸-Ser（112）Bad共定位。这些观察结果表明，Pim-3可以通过磷酸化人结肠癌细胞中的Ser（112）来抑制Bad，因此可以防止细胞凋亡并促进人结肠癌的进展。
We previously observed that Pim-3 with serine/threonine kinase activity, was aberrantly expressed in malignant lesions of endoderm-derived organs, liver and pancreas. Because Pim-3 protein was not detected in normal colon mucosal tissues, we evaluated Pim-3 expression in malignant lesions of human colon, another endoderm-derived organ. Pim-3 was detected immunohistochemically in well-differentiated (43/68 cases) and moderately differentiated (23/41 cases) but not poorly differentiated colon adenocarcinomas (0/5 cases). Moreover, Pim-3 proteins were detected in adenoma (35/40 cases) and normal mucosa (26/111 cases), which are adjacent to adenocarcinoma. Pim-3 was constitutively expressed in SW480 cells and the transfection with Pim-3 short hairpin RNA promoted apoptosis. In the same cell line, a pro-apoptotic molecule, Bad, was phosphorylated at Ser(112) and Ser(136) sites of phosphorylation that are representative of its inactive form. Ser(112) but not Ser(136) phosphorylation in this cell line was abrogated by Pim-3 knockdown. Furthermore, in human colon cancer tissues, Pim-3 co-localized with Bad in all cases (9/9) and with phospho-Ser(112)Bad in most cases (6/9). These observations suggest that Pim-3 can inactivate Bad by phosphorylating its Ser(112) in human colon cancer cells and thus may prevent apoptosis and promote progression of human colon cancer.