翻译起始因子与肿瘤翻译调控异常研究进展

摘要/Abstract

摘要： 蛋白合成是维持细胞稳态和细胞增殖的关键步骤。翻译过程的调控多发生在蛋白合成起始过程,多种翻译起始因子(eIFs)参与此过程。在细胞恶性表型转化过程中,常伴随这些因子的磷酸化、过表达及降解过程异常。如帽结合蛋白eIF4E高表达,甲硫氨酸-tRNA结合蛋白eIF2过度活跃,eIF3的活性增高等现象。eIFs在蛋白合成及细胞增殖过程中的重要地位使得其成为抗肿瘤研究的热点及潜在的治疗靶点。本文对eIFs及肿瘤翻译调控的研究进展及研究方法进行综述。

关键词: 翻译起始因子, 翻译调控, 肿瘤发生, 恶性表型

Abstract: Maintenance of cell homeostasis and regulation of cell proliferation depend importantly on regulating the process of protein synthesis. Most translational controls occur during the initiation phase of protein synthesis recruiting several translation initiation factors (eIFs), with the initiation factors being the major target of regulation through their phosphorylation. When the process of protein synthesis is hyper-activated, abnormalities in the phosphorylation, expression and degradation were frequently observed, leading to an imbalance of cellular proteins that promotes cell proliferation and malignant transformation. This occurs, for example, when the cap-binding protein, eIF4E, is overexpressed, or when the methionyl-tRNAi-binding factor, eIF2, is too active, and when eIF3 hyper-activated. The importance of eIFs as regulators of protein synthesis and cell proliferation makes them potential therapeutic targets for the treatment of cancer. This review focuses on eIFs and mechanisms of translational control and how disregulation results in cell malignancy.

Key words: Translation initiation factors(eIFs), Translation control, Tumorigenesis, Malignant phenotype

中图分类号:

R968

沈杰, 谢海棠, 刘昭前. 翻译起始因子与肿瘤翻译调控异常研究进展[J]. 中国临床药理学与治疗学, 2013, 18(3): 331-338.

SHEN Jie, XIE Hai-tang, LIU Zhao-qian. Translation initiation factors and abnormalities of translation control in tumors[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2013, 18(3): 331-338.

参考文献

[1] Fraser CS. The molecular basis of translational control[J]. Prog Mol Biol Transl Sci,2009,90:1-51.
[2] Watkins SJ, Norbury CJ. Translation initiation and its deregulation during tumorigenesis[J]. Br J Cancer,2002,86(7):1023-1027.
[3] Pestova TV, Kolupaeva VG. The roles of individual eukaryotic translation initiation factors in ribosomal scanning and initiation codon selection[J]. Genes Dev,2002,16(22):2906-2922.
[4] Scheper GC, Proud CG, van der Knaap MS. Defective translation initiation causes vanishing of cerebral white matter[J]. Trends Mol Med, 2006,12(4):159-166.
[5] Kline CL, Schrufer TL, Jefferson LS, et al. Glucosamine-induced phosphorylation of the alpha-subunit of eukaryotic initiation factor 2 is mediated by the protein kinase R-like endoplasmic-reticulum associated kinase[J]. Int J Biochem Cell Biol, 2006,38(5/6):1004-1014.
[6] Malina A, Cencic R, Pelletier J. Targeting translation dependence in cancer[J]. Oncotarget,2011,2(1/2):76-88.
[7] Liu Z, Dong Z, Yang Z, et al. Role of eIF3a (eIF3 p170) in intestinal cell differentiation and its association with early development[J]. Differentiation, 2007,75(7):652-661.
[8] Bitterman PB, Polunovsky VA. Translational control of cell fate: from integration of environmental signals to breaching anticancer defense[J]. Cell Cycle,2012,11(6):1097-1107.
[9] Polunovsky VA, Bitterman PB. The cap-dependent translation apparatus integrates and amplifies cancer pathways[J]. RNA Biol,2006,3(1):10-17.
[10] Jackson RJ, Hellen CU, Pestova TV. The mechanism of eukaryotic translation initiation and principles of its regulation[J]. Nat Rev Mol Cell Biol,2010,11(2):113-127.
[11] Jackson RJ. Alternative mechanisms of initiating translation of mammalian mRNAs[J]. Biochem Soc Trans, 2005,33(Pt 6):1231-1241.
[12] Komar AA, Hatzoglou M. Cellular IRES-mediated translation: the war of ITAFs in pathophysiological states[J]. Cell Cycle, 2011,10(2):229-240.
[13] Palmiter RD. Quantitation of parameters that determine the rate of ovalbumin synthesis[J]. Cell,1975,4(3):189.
[14] Kozak M. Alternative ways to think about mRNA sequences and proteins that appear to promote internal initiation of translation[J]. Gene,2003,318:1-23.
[15] Klinge S, Voigts-Hoffmann F, Leibundgut M, et al. Atomic structures of the eukaryotic ribosome[J]. Trends Biochem Sci, 2012,37(5):189-198.
[16] Audic Y, Hartley RS. Post-transcriptional regulation in cancer[J]. Biol Cell, 2004,96(7):479-498.
[17] Mahoney SJ, Dempsey JM, Blenis J. Cell signaling in protein synthesis ribosome biogenesis and translation initiation and elongation[J]. Prog Mol Biol Transl Sci,2009,90:53-107.
[18] Van Der Kelen K, Beyaert R, Inze D, et al. Translational control of eukaryotic gene expression[J]. Crit Rev Biochem Mol Biol,2009,44(4):143-168.
[19] Firczuk H, Kannambath S, Pahle J, et al. An in vivo control map for the eukaryotic mRNA translation machinery[J]. Mol Syst Biol,2013,9:635.
[20] Asano K, Clayton J, Shalev A, et al. A multifactor complex of eukaryotic initiation factors, eIF1, eIF2, eIF3, eIF5, and initiator tRNA(Met) is an important translation initiation intermediate in vivo[J]. Genes Dev,2000,14(19):2534-2546.
[21] Graff JR, Konicek BW, Carter JH, et al.Targeting the eukaryotic translation initiation factor 4E for cancer therapy[J]. Cancer Res,2008,68(3):631-634.
[22] Konicek BW, Dumstorf CA, Graff JR. Targeting the eIF4F translation initiation complex for cancer therapy[J]. Cell Cycle, 2008,7(16):2466-2471.
[23] Mamane Y, Petroulakis E, Rong L, et al. eIF4E--from translation to transformation[J]. Oncogene, 2004,23(18):3172-3179.
[24] Mamane Y, Petroulakis E, Rong L, et al. eIF4E--from translation to transformation[J]. Oncogene, 2004,23(18):3172-3179.
[25] Fischer PM. Cap in hand: targeting eIF4E[J]. Cell Cycle,2009,8(16):2535-2541.
[26] Lazaris-Karatzas A, Montine KS, Sonenberg N. Malignant transformation by a eukaryotic initiation factor subunit that binds to mRNA 5' cap[J]. Nature, 1990,345(6275):544-547.
[27] Fukuchi-Shimogori T, Ishii I, Kashiwagi K, et al. Malignant transformation by overproduction of translation initiation factor eIF4G[J]. Cancer Res, 1997,57(22):5041-5044.
[28] Coleman LJ, Peter MB, Teall TJ, et al. Combined analysis of eIF4E and 4E-binding protein expression predicts breast cancer survival and estimates eIF4E activity[J]. Br J Cancer, 2009,100(9):1393-1399.
[29] Derry MC, Yanagiya A, Martineau Y, et al. Regulation of poly(A)-binding protein through PABP-interacting proteins[J]. Cold Spring Harb Symp Quant Biol, 2006,71:537-543.
[30] Shuda M, Kondoh N, Tanaka K, et al. Enhanced expression of translation factor mRNAs in hepatocellular carcinoma[J]. Anticancer Res, 2000,20(4):2489-2494.
[31] Lankat-Buttgereit B, Goke R. The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation[J]. Biol Cell,2009,101(6):309-317.
[32] Baird TD, Wek RC. Eukaryotic initiation factor 2 phosphorylation and translational control in metabolism[J]. Adv Nutr,2012,3(3):307-321.
[33] Sonenberg N, Dever TE. Eukaryotic translation initiation factors and regulators[J]. Curr Opin Struct Biol,2003,13(1):56-63.
[34] Koromilas AE, Roy S, Barber GN, et al. Malignant transformation by a mutant of the IFN-inducible dsRNA-dependent protein kinase[J]. Science,1992,257(5077):1685-1689.
[35] Jagus R, Joshi B, Barber GN. PKR, apoptosis and cancer[J]. Int J Biochem Cell Biol, 1999,31(1):123-138.
[36] Anderson P, Kedersha N. Visibly stressed: the role of eIF2, TIA-1, and stress granules in protein translation[J]. Cell Stress Chaperones,2002,7(2):213-221.
[37] Wek RC, Jiang HY, Anthony TG. Coping with stress: eIF2 kinases and translational control[J]. Biochem Soc Trans, 2006,34(Pt 1):7-11.
[38] Clemens MJ. Initiation factor eIF2 alpha phosphorylation in stress responses and apoptosis[J]. Prog Mol Subcell Biol, 2001,27:57-89.
[39] Dalton LE, Healey E, Irving J, et al. Phosphoproteins in stress-induced disease[J]. Prog Mol Biol Transl Sci, 2012,106:189-221.
[40] Donze O, Jagus R, Koromilas AE, et al. Abrogation of translation initiation factor eIF-2 phosphorylation causes malignant transformation of NIH 3T3 cells[J]. EMBO J,1995,14(15):3828-3834.
[41] Damoc E, Fraser CS, Zhou M, et al. Structural characterization of the human eukaryotic initiation factor 3 protein complex by mass spectrometry[J]. Mol Cell Proteomics, 2007,6(7):1135-1146.
[42] Valasek L, Mathew AA, Shin BS, et al. The yeast eIF3 subunits TIF32/a, NIP1/c, and eIF5 make critical connections with the 40S ribosome in vivo[J]. Genes Dev,2003,17(6):786-799.
[43] Hui DJ, Bhasker CR, Merrick WC, et al. Viral stress-inducible protein p56 inhibits translation by blocking the interaction of eIF3 with the ternary complex eIF2.GTP.Met-tRNAi[J]. J Biol Chem,2003,278(41):39477-39482.
[44] Martineau Y, Derry MC, Wang X, et al. Poly(A)-binding protein-interacting protein 1 binds to eukaryotic translation initiation factor 3 to stimulate translation[J]. Mol Cell Biol,2008,28(21):6658-6667.
[45] Park HS, Himmelbach A, Browning KS, et al. A plant viral "reinitiation" factor interacts with the host translational machinery[J]. Cell,2001,106(6):723-733.
[46] Lagirand-Cantaloube J, Offner N, Csibi A, et al. The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy[J]. EMBO J,2008,27(8):1266-1276.
[47] Lee JP, Brauweiler A, Rudolph M, et al. The TRC8 ubiquitin ligase is sterol regulated and interacts with lipid and protein biosynthetic pathways[J]. Mol Cancer Res,2010,8(1):93-106.
[48] Bolger TA, Folkmann AW, Tran EJ, et al. The mRNA export factor Gle1 and inositol hexakisphosphate regulate distinct stages of translation[J]. Cell,2008,134(4):624-633.
[49] Harris TE, Chi A, Shabanowitz J, et al. mTOR-dependent stimulation of the association of eIF4G and eIF3 by insulin[J]. EMBO J,2006,25(8):1659-1668.
[50] Choy L, Derynck R. The type II transforming growth factor (TGF)-beta receptor-interacting protein TRIP-1 acts as a modulator of the TGF-beta response[J]. J Biol Chem, 1998,273(47):31455-31462.
[51] Saletta F, Suryo Rahmanto Y, Richardson DR. The translational regulator eIF3a: the tricky eIF3 subunit![J] Biochim Biophys Acta, 2010,1806(2):275-286.
[52] Dong Z, Liu Z, Cui P, et al. Role of eIF3a in regulating cell cycle progression[J]. Exp Cell Res, 2009,315(11):1889-1894.
[53] Dong Z, Liu LH, Han B, et al. Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth[J]. Oncogene, 2004,23(21):3790-3801.
[54] Yin JY, Shen J, Dong ZZ, et al. Effect of eIF3a on response of lung cancer patients to platinum-based chemotherapy by regulating DNA repair[J]. Clin Cancer Res, 2011,17(13):4600-4609.
[55] Yin JY, Dong ZZ, Liu RY, et al. Translational regulation of RPA2 via internal ribosomal entry site and by eIF3a[J]. Carcinogenesis,2013. [Epub ahead of print]
[56] Yin JY, Dong Z, Liu ZQ, et al. Translational control gone awry: a new mechanism of tumorigenesis and novel targets of cancer treatments[J]. Biosci Rep, 2011,31(1):1-15.
[57] Zhang L, Pan X, Hershey JW. Individual overexpression of five subunits of human translation initiation factor eIF3 promotes malignant transformation of immortal fibroblast cells[J]. J Biol Chem,2007,282(8):5790-5800.
[58] Shi J, Kahle A, Hershey JW, et al. Decreased expression of eukaryotic initiation factor 3f deregulates translation and apoptosis in tumor cells[J]. Oncogene,2006,25(35):4923-4936.
[59] Shi J, Feng Y, Goulet AC, et al. The p34cdc2-related cyclin-dependent kinase 11 interacts with the p47 subunit of eukaryotic initiation factor 3 during apoptosis[J]. J Biol Chem, 2003,278(7):5062-5071.
[60] Shi J, Hershey JW, Nelson MA. Phosphorylation of the eukaryotic initiation factor 3f by cyclin-dependent kinase 11 during apoptosis[J]. FEBS Lett,2009,583(6):971-977.
[61] Miyazaki S, Imatani A, Ballard L, et al. The chromosome location of the human homolog of the mouse mammary tumor-associated gene INT6 and its status in human breast carcinomas[J]. Genomics,1997,46(1):155-158.
[62] Ahlemann M, Zeidler R, Lang S, et al. Carcinoma-associated eIF3i overexpression facilitates mTOR-dependent growth transformation[J]. Mol Carcinog,2006,45(12):957-967.
[63] Kedersha N, Anderson P. Regulation of translation by stress granules and processing bodies[J]. Prog Mol Biol Transl Sci,2009,90:155-185.
[64] Meyuhas O, Dreazen A. Ribosomal protein S6 kinase from TOP mRNAs to cell size[J]. Prog Mol Biol Transl Sci,2009,90:109-153.
[65] Ghosh A, Datta R, Majumdar A, et al. The N-terminal lysine residue-rich domain II and the 340-430 amino acid segment of eukaryotic initiation factor 2-associated glycoprotein p67 are the binding sites for the gamma-subunit of eIF2[J]. Exp Cell Res,2006,312(16):3184-3203.
[66] Guan XY, Fung JM, Ma NF, et al. Oncogenic role of eIF-5A2 in the development of ovarian cancer[J]. Cancer Res,2004,64(12):4197-4200.
[67] Anand N, Murthy S, Amann G, et al. Protein elongation factor EEF1A2 is a putative oncogene in ovarian cancer[J]. Nat Genet,2002,31(3):301-305.