生物谷报道：蛋白质磷酸酶PP2A活性受抑被认为是人类细胞发生恶性转化 的一个先决条件。但是，目前关于PP2A受抑制的分子机制并不清楚。最近，研究人员新发现了一种蛋白是PP2A的抑制剂，这种抑制剂具有致癌活性。研究结果发表在最新一期的《细胞》杂志上。
这种蛋白，被命名为CIP2A，可以和同样具有致癌性的转录因子c-myc直接相互作用，并通过抑制PP2A对c-myc基因第62位四氨酸的作用，因而抑制了c-myc蛋白水解。此外，CIP2A还可以促进停泊不依赖性细胞生长和体内的细胞转化。研究人员通过过表达CIP2A可引起人类细胞转化，从而证明了其具有致癌性。更值得一提的是，研究人员发现在两种常见的人类恶性肿瘤疾病――颅内和颈部鳞状上皮细胞癌，以及结肠癌――中发现了过表达的CIP2A。
这项研究结果证实了CIP2A是一种人类癌蛋白，它可以抑制PP2A在人类恶性肿瘤中的活性，并稳定c-myc的活性。
原文出处：
Cell July 13, 2007: 130 (1)
CIP2A Inhibits PP2A in Human Malignanciesp51
Melissa R. Junttila, Pietri Puustinen, Minna Niemelä, Raija Ahola, Hugh Arnold, Trine Böttzauw, Risto Ala-aho, Christina Nielsen, Johanna Ivaska, Yoichi Taya, Shi-Long Lu, Shujun Lin, Edward K.L. Chan, Xiao-Jing Wang, Reidar Grènman, Juergen Kast, Tuula Kallunki, Rosalie Sears, Veli-Matti Kähäri, and Jukka Westermarck
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作者简介;
Group leader
Jukka Westermarck
Senior Fellow of the Academy of Finland
Biography:
Jukka Westermarck (b. 1969) received his M.D. in 1996 and Ph.D in 1998 at the University of Turku. He was a postdoctoral fellow at European Molecular Biology Laboratory in Heidelberg, Germany, in Dr. Dirk Bohmann´s laboratory during 1999-2001. At 2002 he was appointed to Academy of Finland senior scientist position and works currently as a group leader in Centre for Biotechnology.
Description of the project:
Mitogen-activated protein kinase (MAPK) pathways (ERK, JNK and p38) have been shown to regulate several physiological and pathological cellular phenomena, including inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion and metastasis. However, the molecular mechanisms which determine the specificity of cellular fate after stimulation of different MAPK pathways, are still largely unknown. The ERK1,2 pathway has been shown to stimulate cell growth and oppose the apoptotic effects of JNK/SAPK and p38 pathways suggesting that a finely tuned balance between these pathways is crucial for cell survival and proper control of cell growth. The AP-1 transcription factor c-Jun is a prototypical nuclear effector of JNK MAPK signalling. Both JNK and c-Jun have been implicated in various steps of progression of malignant phenotype of the cell. Nevertheless, the role of JNK and c-Jun in tumor progression is unclear since both can also induce apoptosis.
Regarding the complexity of the responses mediated by MAPK signalling, it would be of great medical and biological relevance to better understand the molecular mechanisms how cell decides which fate to adopt after stimulation of MAPK signalling by e.g. stress stimuli. It is feasible, that formation of signalling and cell-specific multi-protein complexes that interact with components of the MAPK pathways might regulate these responses.
Tandem affinity purification (TAP) method has recently been shown to be a powerful tool for the purification of large protein complexes from yeast under native conditions. Establishment of TAP purification protocol for mammalian cell culture model has allowed purification of multiprotein complexes from a cell line of an interest in vivo. By using the TAP method, we have purified a novel protein complex that interacts with c-Jun in human cancer cell line. To date, the function of two of these proteins has been studied in more detail. Our goal is now to continue the studies concerning the function and role of c-Jun interacting protein complex. In addition, the aim of this research project is to characterise novel protein complexes that bind to components of MAPK pathways, under conditions that regulate the cell fate (e.g. tumor cell invasion and apoptosis), and to examine the role of these protein-protein interactions in the regulation of tumor cell behaviour. Based on its generic nature, TAP method should be widely applicable to the identification of variety of protein-protein interactions in different biological models and in this regard, collaborative projects concerning the utilization of TAP technique have been initiated with other research groups.
Results of this project may reveal new fundamental information about the MAPK and AP-1 signalling and regulation of cancer cell behaviour. In addition these results might provide new insights to the role of protein-protein interactions in cellular signalling.
Funding:
The Academy of Finland, the Turku University Foundation, The Cancer Research Foundation of Southwest Finland, Sigrid Juselius Foundation
Selected Publications:
Mialon A, Sankinen M, Söderström H, Junttila TT, Holmström T, Koivusalo R, Papageorgiou AC, Johnson RS, Hietanen S, Elenius K, Westermarck J; DNA topoisomerase I is a co-factor for c-Jun in the regulation of EGFR expression and cancer cell proliferation. Mol. Cell. Biol., in press 2005.
Junttila MR, Saarinen S, Schmidt T, Kast J, Westermarck J; Single-step Strep-tag Purification for the isolation and identification of protein complexes from mammalian cells. Proteomics, in press 2005.
Li S-P, Junttila MR, Han J, Kähäri V-M, Westermarck J; p38 mitogen-activated protein kinase pathway suppresses cell survival by inducing dephosphorylation of Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase1,2. Cancer Research, 63, 3473-3477,2003.
Westermarck, J., Weiss, C., Saffrich, R., Kast, J., Musti, A.-M., Wessely, M., Ansorge, W., Seraphin, B., Wilm, M., Valdez, B. & Bohmann, D. (2002). DexH/D RNA Helicase RHII/Gu is a novel co-factor for transcription factor c-Jun. EMBO J. 21:451-460.
Westermarck, J., Li, S., Kallunki, T., Han, J.& Kähäri V.-M. (2001). p38 mitogen-activated protein kinase-dependent activation of protein phosphatases 1 and 2A inhibits MEK1 and MEK2 activity and collagenase 1 (MMP-1) gene expression. Mol. Cell. Biol. 21:2373-2383.
Westermarck, J., Li, S., Jaakkola, P., Grenman, R., Kallunki, T. & Kähäri, V.-M. (2000). Activation of Fibroblast Collagenase-1 Expression by Tumor Cells of Squamous Cell Carcinomas is Mediated by p38 Mitogen-Activated Protein Kinase and Jun N-terminal Kinase-2. Cancer Res. 60:7156-7162.
Ivaska, J., Reunanen, H., Westermarck, J., Koivisto, L., Kähäri, V.-M. & Heino, J. (1999). Integrin a2b1 mediates isoform specific activation of p38 and upregulation of collagen gene transcription by a mechanism involving the a2 cytoplasmic tail. J. Cell Biol. 147:401-415.
