Magi-Galluzzi C, Mishra R, Fiorentino M, Montironi R, Yao H, Capodieci P, Wishnow K, Kaplan I, Stork P J, Loda M
Department of Pathology, Deaconess Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Lab Invest. 1997 Jan;76(1):37-51.
Several oncogenes involved in prostate carcinogenesis activate mitogen-activated protein (MAP) kinases, which can relay both proliferative (via extracellular regulated kinases (ERK)) and apoptotic signals (via jun N-terminal protein kinases (JNK)) to the nucleus. Mitogen-activated protein kinase phosphatase 1 (MKP-1) is induced by several oncogenes in the ras-dependent pathway and can inactivate both MAP kinase pathways. The role of MKP-1 in proliferation and apoptosis is, however, still controversial. A series of 51 prostate cancers, including a subset (n = 13) that had been previously treated by androgen ablation, was used to examine whether MKP-1 mRNA and protein expression correlated with that of ERK-1, JNK-1, bcl-2, which confers resistance to apoptosis, and apoptotic index measured by in situ end-labeling of fragmented DNA. In a subset of tumors, MKP-1 expression was assessed by semiquantitative RT-PCR and was compared with both ERK-1 and JNK-1 enzymatic activity. In cases not treated by androgen ablation, MKP-1 was overexpressed in the preinvasive stage of prostate cancer, but its expression decreased with higher histologic grade and advanced disease stage. There was coexpression of MKP-1, ERK-1, and JNK-1 proteins. In addition, MKP-1 expression was inversely correlated to JNK-1 but not to ERK-1 enzymatic activity. Finally, MKP-1 and bcl-2 were inversely related to apoptotic indices. In cases treated by total androgen ablation, MKP-1 and bcl-2 were both down-regulated, whereas JNK-1 was up-regulated. Subpopulations of cells that did not undergo apoptosis maintained expression of both MKP-1 and bcl-2. These results suggest that MKP-1 overexpression is associated with the early phases of neoplastic transformation in prostate tissue. The enzymatic data on MKP-1 kinase substrates and the inverse correlation between MKP-1 and parameters of programmed cell death support the hypothesis that MKP-1 inhibits apoptosis in human prostate tumors, perhaps through the JNK pathway.
一些参与前列腺癌发生的癌基因可激活丝裂原活化蛋白（MAP）激酶，该激酶能将增殖信号（通过细胞外调节激酶（ERK））和凋亡信号（通过Jun氨基末端蛋白激酶（JNK））传递至细胞核。丝裂原活化蛋白激酶磷酸酶1（MKP-1）由ras依赖途径中的几种癌基因诱导产生，可使两条MAP激酶途径失活。然而，MKP-1在增殖和凋亡中的作用仍存在争议。本研究使用了51例前列腺癌病例，包括一部分先前接受过雄激素去除治疗的病例（n = 13），以检测MKP-1 mRNA和蛋白表达是否与ERK-1、JNK-1、bcl-2（赋予细胞凋亡抗性）的表达以及通过DNA片段原位末端标记法测定的凋亡指数相关。在一部分肿瘤中，通过半定量RT-PCR评估MKP-1表达，并与ERK-1和JNK-1酶活性进行比较。在未接受雄激素去除治疗的病例中，MKP-1在前列腺癌的侵袭前期过度表达，但其表达随组织学分级升高和疾病进展而降低。MKP-1、ERK-1和JNK-1蛋白存在共表达。此外，MKP-1表达与JNK-1酶活性呈负相关，但与ERK-1酶活性无关。最后，MKP-1和bcl-2与凋亡指数呈负相关。在接受完全雄激素去除治疗的病例中，MKP-1和bcl-2均下调，而JNK-1上调。未发生凋亡的细胞亚群维持MKP-1和bcl-2的表达。这些结果表明，MKP-1的过度表达与前列腺组织肿瘤转化的早期阶段相关。关于MKP-1激酶底物的酶学数据以及MKP-1与程序性细胞死亡参数之间的负相关支持了以下假说：MKP-1可能通过JNK途径抑制人类前列腺肿瘤中的细胞凋亡。
