Preferences help
enabled [disable] Abstract
Number of results
2010 | 57 | 1 | 15-21
Article title

N-myc downstream regulated 1 gene and its place in the cellular machinery

Title variants
Languages of publication
The exact function of the protein product of N-myc downstream regulated 1 gene (NDRG1) is unclear. Depending on the tissue type the NDRG1 protein is localized in the cytoplasm, nucleus, mitochondrion or membranes. Moreover, the expression of NDRG1 may be altered by several factors such as hypoxia, heavy metals, DNA damage, hormones, oncogene, and tumor-suppressor genes. A number of studies emphasize the role of NDRG1 in cancerogenesis. Presumably NDRG1 participates in angiogenesis, metastases, and mechanisms leading to anti-cancer drug resistance. This review summarizes current knowledge about the NDRG1 gene and the position of NDRG1 protein in the cellular machinery. The role of NDRG1 in cancer pathogenesis and its possible usefulness as a prognostic factor for patients with cancer is also discussed.
Physical description
  • Department of Molecular Medicine, Medical University of Gdańsk, Gdańsk, Poland
  • Department of Molecular Medicine, Medical University of Gdańsk, Gdańsk, Poland
  • Agarwala KL, Kokame K, Kato H, Miyata T (2000) Phosphorylation of RTP, an ER stress-responsive cytoplasmic protein. Biochem Biophys Res Commun 272: 641-647.
  • Ando T, Ishiguro H, Kimura M, Mitsui A, Kurehara H, Sugito N, Tomoda K, Mori R, Takashima N, Ogawa R, Fujii Y, Kuwabara Y (2006) Decreased expression of NDRG1 is correlated with tumor progression and poor prognosis in patients with esophageal squamous cell carcinoma. Dis Esophagus 19: 454-458.
  • Andrew AS, Klei LR, Barchowsky A (2001) Nickel requires hypoxia-inducible factor-1 alpha, not redox signaling, to induce plasminogen activator inhibitor-1. Am J Physiol Lung Cell Mol Physiol 281: L607-L615.
  • Bandyopadhyay S, Pai SK, Gross SC, Hirota S, Hosobe S, Miura K, Saito K, Commes T, Hayashi S, Watabe M, Watabe K (2003) The Drg-1 gene suppresses tumor metastasis in prostate cancer. Cancer Res 63: 1731-1736.
  • Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Takano Y, Saito K, Piquemal D, Commes T, Watabe M, Gross SC, Wang Y, Ran S, Watabe K (2004a) Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene 23: 5675-5681.
  • Bandyopadhyay S, Pai SK, Hirota S, Hosobe S, Tsukada T, Miura K, Takano Y, Saito K, Commes T, Piquemal D, Watabe M, Gross S, Wang Y, Huggenvik J, Watabe K (2004b) PTEN up-regulates the tumor metastasis suppressor gene Drg-1 in prostate and breast cancer. Cancer Res 64: 7655-7660.
  • Barchowsky A, Soucy NV, O'Hara KA, Hwa J, Noreault TL, Andrew AS (2002) A novel pathway for nickel-induced interleukin-8 expression. J Biol Chem 277: 24225-24231.
  • Bernal J, Lee JH, Cribbs LL, Perez-Reyes E (1997) Full reversal of Pb++block of L-type Ca++ channels requires treatment with heavy metal antidotes. J Pharmacol Exp Ther 282: 172-180.
  • Busselberg D (1995) Calcium channels as target sites of heavy metals. Toxicol Lett 82-83: 255-261.
  • Cangul H (2004) Hypoxia upregulates the expression of the NDRG1 gene leading to its overexpression in various human cancers. BMC Genet 5: 27.
  • Cangul H, Salnikow K, Yee H, Zagzag D, Commes T, Costa M (2002) Enhanced overexpression of an HIF-1/hypoxia-related protein in cancer cells. Environ Health Perspect 110 (Suppl 5): 783-788.
  • Cantley LC, Neel BG (1999) New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase AKT pathway. Proc Natl Acad Sci USA 96: 4240-4245.
  • Caruso RP, Levinson B, Melamed J, Wieczorek R, Taneja S, Polsky D, Chang C, Zeleniuch-Jacquotte A, Salnikow K, Yee H, Costa M, Osman I (2004) Altered N-myc downstream-regulated gene 1 protein expression in African-American compared with caucasian prostate cancer patients. Clin Cancer Res 10: 222-227.
  • Chen J, Li S, Yang Z, Lu G, Hu H (2008) Correlation between NDRG1 and PTEN expression in endometrial carcinoma. Cancer Sci 99: 706-710.
  • Chen S, Han YH, Zheng Y, Zhao M, Yan H, Zhao Q, Chen GQ, Li D (2009) NDRG1 contributes to retinoic acid-induced differentiation of leukemic cells. Leuk Res 33: 1108-1113.
  • Chua MS, Sun H, Cheung ST, Mason V, Higgins J, Ross DT, Fan ST, So S (2007) Overexpression of NDRG1 is an indicator of poor prognosis in hepatocellular carcinoma. Mod Pathol 20: 76-83.
  • Cockman ME, Masson N, Mole DR, Jaakkola P, Chang GW, Clifford SC, Maher ER, Pugh CW, Ratcliffe PJ, Maxwell PH (2000) Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 275: 25733-25741.
  • Dahia PML (2000) PTEN, a unique tumor suppressor gene. Endocr Relat Cancer 7: 115-129.
  • Dong Z, Arnold RJ, Yang Y, Park MH, Hrncirova P, Mechref Y, Novotny MV, Zhang JT (2005) Modulation of differentiation-related gene 1 expression by cell cycle blocker mimosine, revealed by proteomic analysis. Mol Cell Proteomics 4: 993-1001.
  • Echaniz-Laguna A, Degos B, Bonnet C, Latour P, Hamadouche T, Lévy N, Leheup B (2007) NDRG1-linked Charcot-Marie-Tooth disease (CMT4D) with central nervous system involvement. Neuromuscul Disord 17: 163-168.
  • Eisenberg E, Greene LE (2007) Multiple roles of auxilin and hsc70 in clathrin-mediated endocytosis. Traffic 8: 640-646.
  • Fotovati A, Fujii T, Yamaguchi M, Kage M, Shirouzu K, Oie S, Basaki Y, Ono M, Yamana H, Kuwano M (2006) 17β-Estradiol induces down-regulation of Cap43/NDRG1/Drg-1, a putative differentiation-related and metastasis suppressor gene, in human breast cancer cells. Clin Cancer Res 12: 3010-3018.
  • Gerber HP, Condorelli F, Park J, Ferrara N (1997) Differential transcriptional regulation of the two vascular endothelial growth factor receptor genes. Flt-1, but not Flk-1/KDR, is up-regulated by hypoxia. J Biol Chem 272: 23659-23667.
  • Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB (2000) Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res 60: 749-755.
  • Inagaki Y, Tang W, Xu HL, Guo Q, Mafune K, Konishi T, Nakata M, Sugawara Y, Kokudo N (2009) Localization of N-myc downstream-regulated gene 1 in gastric cancer tissue. Dig Liver Dis 41: 96-103.
  • Kachhap SK, Faith D, Qian DZ, Shabbeer S, Galloway NL, Pili R, Denmeade SR, DeMarzo AM, Carducci MA (2007) The N-Myc down regulated gene1 (NDRG1) is a Rab4a effector involved in vesicular recycling of E-cadherin. PLoS ONE 2: e844.
  • Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, Blechschmidt K, Angelicheva D, Chandler D, Worsley P, Rosenthal A, King RH, Thomas PK (2000) N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am J Hum Genet 67: 47-58.
  • Kalaydjieva L, Hallmayer J, Chandler D, Savov A, Nikolova A, Angelicheva D, King RH, Ishpekova B, Honeyman K, Calafell F, Shmarov A, Petrova J, Turnev I, Hristova A, Moskov M, Stancheva S, Petkova I, Bittles AH, Georgieva V, Middleton L, Thomas PK (1996) Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24. Nat Genet 14: 214-217.
  • Kim KT, Ongusaha PP, Hong YK, Kurdistani SK, Nakamura M, Lu KP, Lee SW (2004) Function of Drg1/Rit42 in p53-dependent mitotic spindle checkpoint. J Biol Chem 279: 38597-38602.
  • Kobayashi T, Cohen P (1999) Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. Biochem J 339: 319-328.
  • Kokame K, Kato H, Miyata T (1996) Homocysteine-respondent genes in vascular endothelial cells identified by differential display analysis. GRP78/BiP and novel genes. J Biol Chem 271: 29659-29665.
  • Koshiji M, Kumamoto K, Morimura K, Utsumi Y, Aizawa M, Hoshino M, Ohki S, Takenoshita S, Costa M, Commes T, Piquemal D, Harris CC, Tchou-Wong KM (2007) Correlation of N-myc downstream-regulated gene 1 expression with clinical outcomes of colorectal cancer patients of different race/ethnicity. World J Gastroenterol 13: 2803-2810.
  • Kovacevic Z, Fu D, Richardson DR (2008) The iron-regulated metastasis suppressor, Ndrg-1: identification of novel molecular targets. Biochim Biophys Acta 1783: 1981-1992.
  • Kurdistani SK, Arizti P, Reimer CL, Sugrue MM, Aaronson SA, Lee SW (1998) Inhibition of tumor cell growth by RTP/rit42 and its responsiveness to p53 and DNA damage. Cancer Res 58: 4439-4444.
  • Lachat P, Shaw P, Gebhard S, van Belzen N, Chaubert P, Bosman FT (2002) Expression of NDRG1, a differentiation-related gene, in human tissues. Histochem Cell Biol 118: 399-408.
  • Le NT, Richardson DR (2002) The role of iron in cell cycle progression and the proliferation of neoplastic cells. Biochim Biophys Acta 1603: 31-46.
  • Le NT, Richardson DR (2004) 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 104: 2967-2975.
  • Li J, Davidson G, Huang Y, Jiang BH, Shi X, Costa M, Huang C (2004) Nickel compounds act through phosphatidylinositol-3-kinase/Akt-dependent, p70(S6k)-independent pathway to induce hypoxia inducible factor transactivation and Cap43 expression in mouse epidermal Cl41 cells. Cancer Res 64: 94-101.
  • Li J, Kretzner L (2003) 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 250: 91-105.
  • Li S, Chen J, Yang Z, Lu G, Tang H, Hu H (2008) N-myc downstream-regulated gene 1 as a downregulated target gene of PTEN in the controlling of tumourigenesis in endometrioid carcinoma. Indian J Med Res 127: 453-459.
  • Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274: 24147-24152.
  • Madan A, Curtin PT (1993) A 24-base-pair sequence 3' to the human erythropoietin gene contains a hypoxia-responsive transcriptional enhancer. Proc Natl Acad Sci U S A 90: 3928-3932.
  • Malette B, Cherry E, Lagacé M, Bernard M, Gosselin D, Hugo P, Shazand K (2003) Large scale validation of human N-myc downstream-regulated gene (NDRG)-1 expression in endometrium during the menstrual cycle. Mol Hum Reprod 9: 671-679.
  • Maruyama Y, Ono M, Kawahara A, Yokoyama T, Basaki Y, Kage M, Aoyagi S, Kinoshita H, Kuwano M (2006) Tumor growth suppression in pancreatic cancer by a putative metastasis suppressor gene Cap43/NDRG1/Drg-1 through modulation of angiogenesis. Cancer Res 66: 6233-6242.
  • Masuda K, Ono M, Okamoto M, Morikawa W, Otsubo M, Migita T, Tsuneyoshi M, Okuda H, Shuin T, Naito S, Kuwano M (2003) Downregulation of Cap43 gene by von Hippel-Lindau tumor suppressor protein in human renal cancer cells. Int J Cancer 105: 803-810.
  • Maxwell PH, Wiesener MS, Chang GW, Clifford SC, Vaux EC, Cockman ME, Wykoff CC, Pugh CW, Maher ER, Ratcliffe PJ (1999) The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399: 271-275.
  • Motwani M, Sirotnak FM, She Y, Commes T, Schwartz GK (2002) Drg1, a novel target for modulating sensitivity to CPT-11 in colon cancer cells. Cancer Res 62: 3950-3955.
  • Murray JT, Campbell DG, Morrice N, Auld GC, Shpiro N, Marquez R, Peggie M, Bain J, Bloomberg GB, Grahammer F, Lang F, Wulff P, Kuhl D, Cohen P (2004) Exploitation of KESTREL to identify NDRG family members as physiological substrates for SGK1 and GSK3. Biochem J 384: 477-488.
  • Murray JT, Cummings LA, Bloomberg GB, Cohen P (2005) Identification of different specificity requirements between SGK1 and PKBα. FEBS Lett 579: 991-994.
  • Nishio S, Ushijima K, Tsuda N, Takemoto S, Kawano K, Yamaguchi T, Nishida N, Kakuma T, Tsuda H, Kasamatsu T, Sasajima Y, Kage M, Kuwano M, Kamura T (2008) Cap43/NDRG1/Drg-1 is a molecular target for angiogenesis and a prognostic indicator in cervical adenocarcinoma. Cancer Lett 264: 36-43.
  • Ohh M, Park CW, Ivan M, Hoffman MA, Kim TY, Huang LE, Pavletich N, Chau V, Kaelin WG (2000) Ubiquitination of hypoxia-inducible factor requires direct binding to the β-domain of the von Hippel-Lindau protein. Nat Cell Biol 2: 423-427.
  • Okuda T, Higashi Y, Kokame K, Tanaka C, Kondoh H, Miyata T (2004) Ndrg1-deficient mice exhibit a progressive demyelinating disorder of peripheral nerves. Mol Cell Biol 24: 3949-3956.
  • Okuda T, Kokame K, Miyata T (2008) Differential expression patterns of NDRG family proteins in the central nervous system. J Histochem Cytochem 56: 175-182.
  • Omyla-Staszewska J, Deptala A (2003) Topoisomerase I inhibitors - a unique class of antineoplastic agents. Współczesna Onkologia 7: 45-53 (in Polish).
  • Pawelczyk T, Strzelczyk B, Szulc A (2007) The expression level of NDRG1 correlates with overall survival rate of patients with colorectal cancer. Ann Oncol 18 (Suppl 7): vii43.
  • Pflueger D, Rickman DS, Sboner A, Perner S, LaFargue CJ, Svensson MA, Moss BJ, Kitabayashi N, Pan Y, de la Taille A, Kuefer R, Tewari AK, Demichelis F, Chee MS, Gerstein MB, Rubin MA (2009) N-myc downstream regulated gene 1 (NDRG1) is fused to ERG in prostate cancer. Neoplasia 11: 804-811.
  • Piquemal D, Joulia D, Balaguer P, Basset A, Marti J, Commes T (1999) Differential expression of the RTP/Drg1/Ndr1 gene product in proliferating and growth arrested cells. Biochim Biophys Acta 1450: 364-373.
  • Qu X, Zhai Y, Wei H, Zhang C, Xing G, Yu Y, He F (2002) Characterization and expression of three novel differentiation-related genes belong to the human NDRG gene family. Mol Cell Biochem 229: 35-44.
  • Rutherford MN, Bayly GR, Matthews BP, Okuda T, Dinjens WM, Kondoh H, LeBrun DP (2001) The leukemogenic transcription factor E2a-Pbx1 induces expression of the putative N-myc and p53 target gene NDRG1 in Ba/F3 cells. Leukemia 15: 362-370.
  • Salnikow K, Kluz T, Costa M (1999) Role of Ca(2+) in the regulation of nickel-inducible Cap43 gene expression. Toxicol Appl Pharmacol 160: 127-132.
  • Salnikow K, Kluz T, Costa M, Piquemal D, Demidenko ZN, Xie K, Blagosklonny MV (2002) 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 22: 1734-1741.
  • Segawa T, Nau ME, Xu LL, Chilukuri RN, Makarem M, Zhang W, Petrovics G, Sesterhenn IA, McLeod DG, Moul JW, Vahey M, Srivastava S (2002) Androgen-induced expression of endoplasmic reticulum (ER) stress response genes in prostate cancer cells. Oncogene 21: 8749-8758.
  • Semenza GL (1999) Regulation of mammalian O2 homeostasis by hypoxia-inducible factor 1. Annu Rev Cell Dev Biol 15: 551-578.
  • Shah MA, Kemeny N, Hummer A, Drobnjak M, Motwani M, Cordon-Cardo C, Gonen M, Schwartz GK (2005) Drg1 expression in 131 colorectal liver metastases: correlation with clinical variables and patient outcomes. Clin Cancer Res 11: 3296-3302.
  • Shaw E, McCue LA, Lawrence CE, Dordick JS (2002) Identification of a novel class in the alpha/beta hydrolase fold superfamily: the N-myc differentiation-related proteins. Proteins 47: 163-168.
  • Shimono A, OkudaT, Kondoh H (1999) 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 83: 39-52.
  • Sibold S, Roh V, Keogh A, Studer P, Tiffon C, Angst E, Vorburger SA, Weimann R, Candinas D, Stroka D (2007) Hypoxia increases cytoplasmic expression of NDRG1, but is insufficient for its membrane localization in human hepatocellular carcinoma. FEBS Lett 581: 989-94.
  • Song Y, Oda Y, Hori M, Kuroiwa K, Ono M, Hosoi F, Basaki Y, Tokunaga S, Kuwano M, Naito S, Tsuneyoshi M (2010) N-myc downstream regulated gene-1/Cap43 may play an important role in malignant progression of prostate cancer, in its close association with E-cadherin. Hum Pathol 41: 214-222.
  • Stein S, Thomas EK, Herzog B, Westfall MD, Rocheleau JV, Jackson RS, Wang M, Liang P (2004) NDRG1 is necessary for p53-dependent apoptosis. J Biol Chem 279: 48930-48940.
  • Strzelczyk B, Szulc A, Rzepko R, Kitowska A, Skokowski J, Szutowicz A, Pawelczyk T (2009) Identification of high-risk stage II colorectal tumors by combined analysis of the NDRG1 gene expression and the depth of tumor invasion. Ann Surg Oncol 16: 1287-1294.
  • Sugiki T, Murakami M, Taketomi Y, Kikuchi-Yanoshita R, Kudo I (2004a) N-myc downregulated gene 1 is a phosphorylated protein in mast cells. Biol Pharm Bull 27: 624-627.
  • Sugiki T, Taketomi Y, Kikuchi-Yanoshita R, Murakami M, Kudo I (2004b) Association of N-myc downregulated gene 1 with heat-shock cognate protein 70 in mast cells. Biol Pharm Bull 27: 628-633.
  • Sun B, Chu D, Li W, Chu X, Li Y, Wei D, Li H (2009) Decreased expression of NDRG1 in glioma is related to tumor progression and survival of patients. J Neurooncol 94: 213-219.
  • Taketomi Y, Sugiki T, Saito T, Ishii S, Hisada M, Suzuki-Nishimura T, Uchida MK, Moon TC, Chang HW, Natori Y, Miyazawa S, Kikuchi-Yanoshita R, Murakami M, Kudo I (2003) Identification of NDRG1 as an early inducible gene during in vitro maturation of cultured mast cells. Biochem Biophys Res Commun 306: 339-346.
  • Tarabová B, Kurejová M, Sulová Z, Drabová M, Lacinová L (2006) Inorganic mercury and methylmercury inhibit the Cav3.1 channel expressed in human embryonic kidney 293 cells by different mechanisms. J Pharmacol Exp Ther 317: 418-427.
  • Tu LC, Yan X, Hood L, Lin B (2007) Proteomics analysis of the interactome of N-myc downstream regulated gene 1 and its interactions with the androgen response program in prostate cancer cells. Mol Cell Proteomics 6: 575-588.
  • Ulrix W, Swinnen JV, Heyns W, Verhoeven G (1999) The differentiation-related gene 1, Drg1, is markedly upregulated by androgens in LNCaP prostatic adenocarcinoma cells. FEBS Lett 455: 23-26.
  • Unoki M, Nakamura Y (2001) Growth-suppressive effects of BPOZ and EGR2, two genes involved in the PTEN signaling pathway. Oncogene 20: 4457-4465.
  • Walmsley SR, McGovern NN, Whyte MK, Chilvers ER (2008) The HIF/VHL pathway: from oxygen sensing to innate immunity. Am J Respir Cell Mol Biol 38: 251-255.
  • Wang Z, Wang F, Wang WQ, Gao Q, Wei WL, Yang Y, Wang GY (2004) Correlation of N-myc downstream-regulated gene 1 overexpression with progressive growth of colorectal neoplasm. World J Gastroenterol 10: 550-554.
  • van Roy F, Berx G (2008) The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci 65: 3756-3788.
  • Yan X, Chua MS, Sun H, So S (2008) N-Myc down-regulated gene 1 mediates proliferation, invasion, and apoptosis of hepatocellular carcinoma cells. Cancer Lett 262: 133-142.
  • Zamponi GW, Bourinet E, Snutch TP (1996) Nickel block of a family of neuronal calcium channels: subtype- and subunit-dependent action at multiple sites. J Membr Biol 151: 77-90.
  • Zhang A-H, Rao JN, Zou T, Liu L, Marasa BS, Xiao L, Chen J, Turner DJ, Wang J-Y (2007) p53-dependent NDRG1 expression induces inhibition of intestinal epithelial cell proliferation but not apoptosis after polyamine depletion. Am J Physiol Cell Physiol 293: C379-C389.
  • Zhang J, Chen S, Zhang W, Zhang J, Liu X, Shi H, Che H, Wang W, Li F, Yao L (2008) Human differentiation-related gene NDRG1 is a Myc downstream-regulated gene that is repressed by Myc on the core promoter region. Gene 417: 5-12.
  • Zhou D, Salnikow K, Costa M (1998) Cap43, a novel gene specifically induced by Ni2+compounds. Cancer Res 58: 2182-2189.
  • Zhou RH, Kokame K, Tsukamoto Y, Yutani C, Kato H, Miyata T (2001) Characterization of the human NDRG gene family: a newly identified member, NDRG4, is specifically expressed in brain and heart. Genomics 73: 86-97.
  • Zinsmaier KE, Bronk P (2001) Molecular chaperones and the regulation of neurotransmitter exocytosis. Biochem Pharmacol 62: 1-11.
  • Zoroddu MA, Kowalik-Jankowska T, Kozlowski H, Salnikow K, Costa M (2001) Ni(II) and Cu(II) binding with a 14-aminoacid sequence of Cap43 protein, TRSRSHTSEGTRSR. J Inorg Biochem 84: 47-54.
Document Type
Publication order reference
YADDA identifier
JavaScript is turned off in your web browser. Turn it on to take full advantage of this site, then refresh the page.