NDRG2: a Myc-repressed gene involved in cancer and cell stress
Corresponding Author
Libo Yao
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
*Corresponding author: Tel, 86-29-84774513; Fax, 86-29-84774513; E-mail, [email protected]Search for more papers by this authorJian Zhang
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
Search for more papers by this authorXuewu Liu
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
Search for more papers by this authorCorresponding Author
Libo Yao
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
*Corresponding author: Tel, 86-29-84774513; Fax, 86-29-84774513; E-mail, [email protected]Search for more papers by this authorJian Zhang
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
Search for more papers by this authorXuewu Liu
The Institute of Molecular Biology and the State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an 710032, China
Search for more papers by this authorThis work was supported by grants from the Changjiang Scholars and Innovative Research Team in Universities of China (No. PCSIRT0459) and the National Natural Science Foundation of China (Nos. 30228012, 30370315, 30570676, 30670452, 30700416 and 06G092)
Abstract
As a master switch for cell proliferation and differentiation, Myc exerts its biological functions mainly through transcrip-tional regulation of its target genes, which are involved in cells' interaction and communication with their external environment. The N-Myc downstream-regulated gene (NDRG) family is composed of NDRG1, NDRG2, NDRG3 and NDRG4, which are important in cell proliferation and differentiation. This review summarizes the recent studies on the structure, tissue distribution and functions of NDRG2 that try to show its significance in studying cancer and its therapeutic potential.
References
- 1 Vervoorts J, Lüscher-Firzlaff J, Lüscher B. The ins and outs of Myc regulation by posttranslational mechanisms. J Biol Chem 2006, 281: 34725–34729.
- 2 Grandori C, Cowley SM, James LP, Eisenman RN. The Myc/Max/Mad network and the transcriptional control of cell behavior. Annu Rev Cell Dev Biol 2000, 16: 653–699.
- 3 Dang CV. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol 1999, 19: 1–11.
- 4 O'Connell BC, Cheung AF, Simkevich CP, Tam W, Ren X, Mateyak MK, Sedivy JM. A large scale genetic analysis of c-Myc-regulated gene expression patterns. J Biol Chem 2003, 278: 12563–12573.
- 5 Deng Y, Yao L, Chau L, Ng SS, Peng Y, Liu X, Au WS et al. N-Myc downstream-regulated gene 2 (NDRG2) inhibits glioblastoma cell proliferation. Int J Cancer 2003, 106: 342–347.
- 6 Okuda T, Kondoh H. Identification of new genes ndr2 and ndr3 which are related to Ndr1/RTP/Drg1 but show distinct tissue specificity and response to N-myc. Biochem Biophys Res Commun 1999, 266: 208–215.
- 7 Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F. Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem 2002, 229: 35–44.
- 8 Kokame K, Kato H, Miyata T. Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. J Biol Chem 1996, 271: 29659–29665.
- 9 Van Belzen N, Dinjens WN, Diesveld MP, Groen NA, Van Der Made AC, Nozawa Y, Vlietstra R et al. A novel gene which is up-regulated during colon epithelial cell differentiation and down-regulated in colorectal neoplasms. Lab Invest 1997, 77: 85–92.
- 10 Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW. Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res 1998, 58: 4439–4444.
- 11 Shimono A, Okuda T, Kondoh H. N-myc-dependent repression of ndr1, a gene identified by direct subtraction of whole mouse embryo cDNAs between wild type and N-myc mutant. Mech Dev 1999, 83: 39–52.
- 12 Zhao W, Tang R, Huang Y, Mao Y. Cloning and expression pattern of the human NDRG3 gene. Biochim Biophys Acta 2001, 1519: 134–38.
- 13 Zhou RH, Kokame K, Tsukamoto Y, Miyata T. Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 2001, 73: 86–97.
- 14 Ohki T, Hongo S, Nakada N, Maeda A, Takeda M. Inhibition of neurite outgrowth by reduced level of NDRG4 protein in antisense transfected PC12 cells. Brain Res Dev Brain Res 2002, 135: 55–63.
- 15 Kovacevic Z, Richardson DR. The metastasis suppressor, Ndrg-1: a new ally in the fight against cancer. Carcinogenesis 2006, 27: 2355–2366.
- 16 Ellen TP, Ke Q, Zhang P, Costa M. NDRG1, a growth and cancer related gene: regulation of gene expression and function in normal and disease states. Carcinogenesis 2008, 29: 2–8.
- 17 Deng YC, Yao LB, Liu XP, Nie XY, Wang JC, Zhang XG, Su CZ. Exploring a new gene containing ACP like domain in human brain and expression it in E coli.. Biochem Biophys Res Commun 2001, 28: 72–76.
- 18 Boulkroun S, Fay M, Zennaro MC, Escoubet B, Jaisser F, Blot-Chabaud M, Farman N et al. Characterization of rat NDRG2 (N-Myc downstream regulated gene 2), a novel early mineralocorti-coid-specific induced gene. J Biol Chem 2002, 277: 31506–31515.
- 19 Maeda A, Hongo S, Miyazaki A. Genomic organization, expression, and comparative analysis of noncoding region of the rat Ndrg4 gene. Gene 2004, 324: 149–158.
- 20 Qu X, Jia H, Garrity DM, Tompkins K, Batts L, Appel B, Zhong TP et al. Ndrg4 is required for normal myocyte proliferation during early cardiac development in zebrafish. Dev Biol 2008, 317: 486–496.
- 21 Kyuno J, Fukui A, Michiue T, Asashima M. Identification and characterization of Xenopus NDRG1. Biochem Biophys Res Commun 2003, 309: 52–57.
- 22 Krauter-Canham R, Bronner R, Evrard JL, Hahne G, Friedt W, Steinmetz A. A transmitting tissue-and pollen-expressed protein from sunflower with sequence similarity to the human RTP protein. Plant Sci 1997, 129: 191–202.
- 23 Joint Center for Structural Genomics. Crystal structure of N-myc downstream regulated 2 (15277975) from Mus musculus at 1.70 Å resolution. RCSB Protein Data Bank (http://www.pdb.org/pdb), 2008.
- 24 Wagner UG, Hasslacher M, Griengl H, Schwab H, Kratky C. Mechanism of cyanogenesis: the crystal structure of hydroxynitrile lyase from Hevea brasiliensis. Structure 1996, 4: 811–822.
- 25 Burchfield JG, Lennard AJ, Narasimhan S, Hughes WE, Wasinger VC, Corthals GL, Okuda T et al. Akt mediates insulin-stimulated phosphorylation of Ndrg2: evidence for cross-talk with protein kinase C theta. J Biol Chem 2004, 279: 18623–18632.
- 26 Murray JT, Campbell DG, Morrice N, Auld GC, Shpiro N, Marquez R, Peggie M et al. Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem J 2004, 384: 477–488.
- 27 Chen WQ, Hoeger H, Diao WF, Pollak A, Lubec G. Mass spectrometrical characterization of NDRG2 protein (N-myc-down-stream regulated gene 2) and description of two novel phosphory-lation sites. Neurochem Res 2007, 32: 1969–1977.
- 28 Lachat P, Shaw P, Gebhard S, Van Belzen N, Chaubert P, Bosman FT. Expression of NDRG1, a differentiation-related gene, in human tissues. Histochem Cell Biol 2002, 118: 399–408.
- 29 Wakisaka Y, Furuta A, Masuda K, Morikawa W, Kuwano M, Iwaki T. Cellular distribution of NDRG1 protein in the rat kidney and brain during normal postnatal development. J Histochem Cytochem 2003, 51: 1515–1525.
- 30 Hu X, Liu X, Deng Y, Lin S, Wu L, Zhang J, Wang L et al. Expression analysis of the NDRG2 gene in mouse embryonic and adult tissues. Cell Tissue Res 2006, 325: 67–76.
- 31 Shen L, Zhao Z, Wang Y, Liu X, Che H, Lin W, Ji S et al. Immuno-histochemical detection of Ndrg2 in the mouse nervous system. Neuroreport 2008, 19: 927–931.
- 32 Okuda T, Kokame K, Miyata T. Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem 2008, 56: 175–182.
- 33 Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB. Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer, Cancer Res 2000, 60: 749–755.
- 34 Wang L, Liu N, Yao L, Li F, Zhang J, Deng Y, Liu J et al. NDRG2 is a new HIF-1 target gene necessary for hypoxia-induced apoptosis in A549 Cells. Cell Physiol Biochem 2008, 21: 239–250.
- 35 Sugiki T, Murakami M, Taketomi Y, Kikuchi-Yanoshita R, Kudo I. Association of N-myc downregulated gene 1 with heat-shock cognate protein 70 in mast cells. Biol Pharm Bull 2004, 27: 628–633.
- 36 Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D et al. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene 2004, 23: 5675–5681.
- 37 Bandyopadhyay S, Wang Y, Zhan R, Pai SK, Watabe M, Iiizumi M, Furuta E et al. The tumor metastasis suppressor gene Drg-1 down-regulates the expression of activating transcription factor 3 in prostate cancer. Cancer Res 2006, 66: 11983–11990.
- 38 Piquemal D, Joulia D, Balaguer P, Basset A, Marti J, Commes T. Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells. Biochim Biophys Acta 1999, 1450: 364–373.
- 39 Angst E, Sibold S, Tiffon C, Weimann R, Gloor B, Candinas D, Stroka D. Cellular differentiation determines the expression of the hypoxia-inducible protein NDRG1 in pancreatic cancer. Br J Cancer 2006, 95: 307–313.
- 40 Gomez-Casero E, Navarro M, Rodriguez-Puebla ML, Larcher F, Paramio JM, Conti CJ, Jorcano JL. Regulation of the differentiation-related gene Drg-1 during mouse skin carcinogenesis. Mol Carcinog 2001, 32: 100–109.
- 41 Lusis EA, Watson MA, Chicoine MR, Lyman M, Roerig P, Reifenberger G, Gutmann DH et al. Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 2005, 65: 7121–7126.
- 42 Lorentzen A, Vogel LK, Lewinsky RH, Saebo M, Skjelbred CF, Godiksen S, Hoff G et al. Expression of NDRG2 is down-regulated in high-risk adenomas and colorectal carcinoma. BMC Cancer 2007, 7: 192–198.
- 43 Choi SC, Yoon SR, Park YP, Song EY, Kim JW, Kim WH, Yang Y et al. Expression of NDRG2 is related to tumor progression and survival of gastric cancer patients through Fas-mediated cell death. Exp Mol Med 2007, 39: 705–714.
- 44 Liu N, Wang L, Liu X, Yang Q, Zhang J, Zhang W, Wu Y et al. Promoter methylation, mutation, and genomic deletion are involved in the decreased NDRG2 expression levels in several cancer cell lines. Biochem Biophys Res Commun 2007, 358: 164–169.
- 45 Hu XL, Liu XP, Lin SX, Deng YC, Liu N, Li X, Yao LB. NDRG2 expression and mutation in human liver and pancreatic cancers. World J Gastroenterol 2004, 10: 3518–3521.
- 46 Assämäki R, Sarlomo-Rikala M, Lopez-Guerrero JA, Lasota J, Andersson LC, Llombart-Bosch A, Miettinen M et al. Array comparative genomic hybridization analysis of chromosomal imbalances and their target genes in gastrointestinal stromal tumors. Genes Chromosomes Cancer 2007, 46: 564–576.
- 47 Felsberg J, Yan PS, Huang TH, Milde U, Schramm J, Wiestler OD, Reifenberger G et al. DNA methylation and allelic losses on chromosome arm 14q in oligodendroglial tumours. Neuropathol Appl Neurobiol 2006, 32: 517–524.
- 48 Hummerich L, Müller R, Hess J, Kokocinski F, Hahn M, Fürstenberger G, Mauch C et al. Identification of novel tumour-associated genes differentially expressed in the process of squamous cell cancer development. Oncogene 2006, 25: 111–121.
- 49 Ulrix W, Swinnen JV, Heyns W, Verhoeven G. The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells. FEBS Lett 1999, 455: 23–26.
- 50 Koshiji M, Kumamoto K, Morimura K, Utsumi Y, Aizawa M, Hoshino M, Ohki S et al. Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. World J Gastroenterol 2007, 13: 2803–2810.
- 51 Schmitt CA, Fridman JS, Yang M, Baranov E, Hoffman RM, Lowe SW. Dissecting p53 tumor suppressor functions in vivo. Cancer Cell 2002, 1: 289–298.
- 52 Wu GQ, Liu XP, Wang LF, Zhang WH, Zhang J, Li KZ, Dou KF et al. Induction of apoptosis of HepG2 cells by NDRG2. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 2003, 19: 357–360.
- 53 Park Y, Shon SK, Kim A, Kim KI, Yang Y, Cho DH, Lee MS et al. SOCS1 induced by NDRG2 expression negatively regulates STAT3 activation in breast cancer cells. Biochem Biophys Res Commun 2007, 363: 361–367.
- 54 Zhang W, Liu X, Wang Y, Han Y, Yao L. Bioinformatic analysis of ndrg2 and NDRG2 protein. Journal of the Fourth Military Medical University 2003, 24: 1537–1539.
- 55 Svensson E, Vidovic K, Olofsson T, Vallon-Christersson J, Borg A, Gullberg U. The Wilms' tumor gene 1 (WT1) induces expression of the N-myc downstream regulated gene 2 (NDRG2). DNA Cell Biol 2007, 26: 589–597.
- 56 Nichols NR. Ndrg2, a novel gene regulated by adrenal steroids and antidepressants, is highly expressed in astrocytes. Ann N Y Acad Sci 2003, 1007: 349–356.
- 57 Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, Wang M et al. NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem 2004, 279: 48930–48940.
- 58 Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW. Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint. J Biol Chem 2004, 279: 38597–38602.
- 59 Rutherford MN, Bayly GR, Matthews BP, Okuda T, Dinjens WM, Kondoh H, LeBrun DP. The leukemogenic transcription factor E2a-Pbx1 induces expression of the putative N-myc and p53 target gene NDRG1 in Ba/F3 cells. Leukemia 2001, 15: 362–370.
- 60 Le NT, Richardson DR. Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation. Blood 2004, 104: 2967–2975.
- 61 Sibold S, Roh V, Keogh A, Studer P, Tiffon C, Angst E, Vorburger SA et al. Hypoxia increases cytoplasmic expression of NDRG1, but is insufficient for its membrane localization in human hepatocellular carcinoma. FEBS Lett 2007, 581: 989–994.
- 62 Li J, Kretzner L. The growth-inhibitory Ndrg1 gene is a Myc negative target in human neuroblastomas and other cell types with overexpressed N- or c-myc. Mol Cell Biochem 2003, 250: 91–105.
- 63 Zhang J, Li F, Liu X, Shen L, Liu J, Su J, Zhang W et al. The repression of human differentiation-related gene NDRG2 expression by Myc via Miz-1-dependent interaction with the NDRG2 core promoter. J Biol Chem 2006, 281: 39159–39168.
- 64 Zhou D, Salnikow K, Costa M. Cap43, a novel gene specifically induced by Ni2+ compounds. Cancer Res 1998, 58: 2182–2189.
- 65 Chen B, Nelson DM, Sadovsky Y. N-myc down-regulated gene 1 modulates the response of term human trophoblasts to hypoxic injury. J Biol Chem 2006, 281: 2764–2772.
- 66 Cangul H. Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet 2004, 5: 27.
- 67 Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV. The regulation of hypoxic genes by calcium involves c-Jun/AP-1, which cooperates with hypoxia-inducible factor 1 in response to hypoxia. Mol Cell Biol 2002, 22: 1734–1741.
- 68 Zhang J, Liu J, Li X, Li F, Wang L, Zhang J, Liu X et al. The physical and functional interaction of NDRG2 with MSP58 in cells. Biochem Biophys Res Commun 2007, 352: 6–11.
- 69 Fabbro M, Henderson BR. Regulation of tumor suppressors by nuclear-cytoplasmic shuttling. Exp Cell Res 2003, 282: 59–69.
- 70 Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, De Jonge R, Blechschmidt K et al. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 2000, 67: 47–58.
- 71 Hunter M, Bernard R, Freitas E, Boyer A, Morar B, Martins IJ, Tournev I et al. Mutation screening of the N-myc downstream-regulated gene 1 (NDRG1) in patients with Charcot-Marie-Tooth Disease. Hum Mutat 2003, 22: 129–135.
- 72 Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T. Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves. Mol Cell Biol 2004, 24: 3949–3956.
- 73 Hirata K, Masuda K, Morikawa W, He JW, Kuraoka A, Kuwano M, Kawabuchi M. N-myc downstream-regulated gene 1 expression in injured sciatic nerves. Glia 2004, 47: 325–334.
- 74 Mitchelmore C, Buchmann-Moller S, Rask L, West MJ, Troncoso JC, Jensen NA. NDRG2: a novel Alzheimer's disease associated protein. Neurobiol Dis 2004, 16: 48–58.
- 75 Takahashi K, Yamada M, Ohata H, Momose K, Higuchi T, Honda K, Yamada M. Expression of Ndrg2 in the rat frontal cortex after antidepressant and electroconvulsive treatment. Int J Neuropsychopharmacol 2005, 8: 381–389.
- 76 Takahashi K, Yamada M, Ohata H, Honda K, Yamada M. Ndrg2 promotes neurite outgrowth of NGF-differentiated PC12 cells. Neurosci Lett 2005, 388: 157–162.
- 77 Hongo S, Watanabe T, Takahashi K, Miyazaki A. Ndrg4 enhances NGF-induced ERK activation uncoupled with Elk-1 activation. J Cell Biochem 2006, 98: 185–193.
- 78 Bhaduri A, Krishnaswamy L, Ullal GR, Panicker MR, Sowdhamini R. Fold prediction and comparative modeling of Bdm1: a probable alpha/beta hydrolase associated with hot water epilepsy. J Mol Model 2003, 9: 3–8.
- 79 Wielpütz MO, Lee IH, Dinudom A, Boulkroun S, Farman N, Cook DI, Korbmacher C et al. (NDRG2) Stimulates amiloride-sensitive Na+ currents in Xenopus laevis oocytes and fisher rat thyroid cells. J Biol Chem 2007, 282: 28264–28273.
- 80 Choi SC, Kim KD, Kim JT, Kim JW, Yoon DY, Choe YK, Chang YS et al. Expression and regulation of NDRG2 (N-myc downstream regulated gene 2) during the differentiation of dendritic cells. FEBS Lett 2003, 53: 413–418.
- 81 Choi SC, Kim KD, Kim JT, Kim JW, Lee HG, Kim JM, Jang YS et al. Expression of human NDRG2 by myeloid dendritic cells inhibits down-regulation of activated leukocyte cell adhesion molecule (ALCAM) and contributes to maintenance of T cell stimulatory activity. J Leukoc Biol 2008, 83: 89–98.
- 82 Sugiki T, Murakami M, Taketomi Y, Kikuchi-Yanoshita R, Kudo I. N-myc downregulated gene 1 is a phosphorylated protein in mast cells. Biol Pharm Bull 2004, 27: 624–627.
- 83 Taketomi Y, Sugiki T, Saito T, Ishii S, Hisada M, Suzuki-Nishimura T, Uchida MK et al. Identification of NDRG1 as an early inducible gene during in vitro maturation of cultured mast cells. Biochem Biophys Res Commun 2003, 306: 339–346.