Homeobox protein NANOG 2672374 225997159 2008-07-16T11:13:03Z Boghog2 2428506 added group abbreviation to TF navbox template {{dablink|See [[NANOG (computing)]] for the network operators' group.}} {{PBB|geneid=79923}} '''NANOG''' (pron. nanOg) is a [[Transcription (genetics)|transcription]] factor critically involved with self-renewal of undifferentiated [[embryonic stem cell]]s. ==Background information== ===Embryonic stem cells=== NANOG is a gene expressed in [[embryonic stem cell]]s (ESCs) and is thought to be a key factor in maintaining [[pluripotency]]. NANOG is thought to function in concert with other factors such as [[Oct-4|POU5F1]] and [[SOX2]] to establish ESC identity. These cells offer an important area of study because of their ability to maintain pluripotency. In other words, these cells have the ability to become virtually any cell of any of the three germ layers ([[endoderm]], [[ectoderm]], [[mesoderm]]). It is for this reason that understanding the mechanisms that maintain a cell's pluripotency is critical for researchers to understand how stem cells work; and may lead to future advances in treating degenerative diseases. ===History=== Dr Ian Chambers (currently of the Institute for Stem Cell Research, The [[University of Edinburgh]], UK) who isolated the mouse Nanog gene said: "Nanog seems to be a master gene that makes embryonic stem cells grow in the laboratory. In effect this makes stem cells immortal. Being Scottish, I therefore chose the name after the [[Tir_na_n-Og|Tir na nOg legend]]."<ref>{{cite web |url=http://www.sciencedaily.com/releases/2003/06/030602024530.htm |title=ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth |accessdate=2007-07-26 |format= |work=}}</ref> ===Genes that code for NANOG=== Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as [[OCT4]], NANOG and REX1. Derived human ESC lines also expressed specific pluripotency markers: *TRA-1-60 *TRA-1-81 *SSEA4 *alkaline phosphatase *TERT *REX1 These markers allowed for the differentiation ''in vitro'' and ''in vivo'' conditions into derivatives of all three germ layers. <ref>Zhang X, Stojkovic P., Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M. Derivation of human embryonic stem cells from developing and arrested embryos. Stem Cells.[http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16990582&query_hl=3&itool=pubmed_docsum]</ref> POU5F1 ([[OCT4]]), TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation. <ref>{{cite journal |author=Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S |title=Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan |journal=Stem Cells Dev. |volume=15 |issue=4 |pages=532–55 |year=2006 |pmid=16978057 |doi=10.1089/scd.2006.15.532}}</ref> ===NANOG protein=== Human NANOG protein (Accession number [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=153945816 NP_079141]) is a 305 amino acid protein with a conserved homeodomain motif that is localized to the nuclear component of cells. The homeodomain facilitates DNA binding. There are N-terminal, homeodomain, and C-terminal region in human NANOG protein. Like murine NANOG, N-terminal region of human NANOG is rich in Ser, Thr and Pro residues and C-terminus contains W repeats. The homeodomain in hNANOG ranges from a.a.95 to a.a 155. The conserved sequence of homeodomain are a.a. 99-100, 102, 106-107, 110, 114, 119, 121, 127-128, 132, 134, 138-140, 142-145, 147, 149, and 151-152. ==Current research== ===Molecular biology=== Overexpression of Nanog in mouse embryonic stem cells causes them to self-renew in the absence of [[Leukemia inhibitory factor]]. In the absence of Nanog, mouse embryonic stem cells differentiate into visceral/parietal endoderm (Chambers et al, 2003 and Mitsui et al, 2003) Loss of Nanog function causes differentiation of embryonic stem cells into other cell types (Lin et al, 2005). NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent.<ref>Darr H, Mayshar Y, Benvenisty N. Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. Development. 2006 Mar;133(6):1193-201.[http://dev.biologists.org/cgi/content/full/133/6/1193]</ref> Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.<ref>Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ. High-efficiency RNA interference in human embryonic stem cells. Stem Cells. 2005 Mar;23(3):299-305.[http://stemcells.alphamedpress.org/cgi/content/full/23/3/299]</ref> It has been shown that the tumour suppressor [[p53]] binds to the promoter of ''NANOG'' and suppresses its expression after DNA damage in mouse embryonic stem cells. p53 can thus induce differentiation of embronic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and [[apoptosis]]. (Lin et al, 2005) Nanog transforms [[3T3 cells|NIH3T3 cells]]. By using [[DNA microarray]] to find the transcription targets of Nanog, Nanog regulated genes have been identified . Some of these target genes explain the [[transformation]] of NIH3T3 cells. (Piestun et al, 2006) GATA6 and Nanog have been linked due to the similar cellular differentiation of ES cells in their absence, which leads to the hypothesis that Nanog may prevent ectodermal growth via repressing GATA6.<ref>Yates A, Chambers I. The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells. Biochem Soc Trans. 2005 Dec;33 (Pt 6):1518-21 [http://www.biochemsoctrans.org/bst/033/1518/bst0331518.htm]</ref> Yamanaka et al., demonstrate [[Induced Pluripotent Stem Cell|induction of pluripotent stem cells]] from mouse embryonic or adult fibroblasts by introducing four factors, Oct3/4, Sox2, c-Myc, and Klf4, under ES cell culture conditions. Of these four factors it has been shown that Nanog was dispensable for such induction in this cell system.<ref> Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors. Cell, Vol 126, 663-676, 25 August 2006.[http://www.cell.com/content/article/abstract?uid=PIIS0092867406009767]</ref> ===Clinical medicine=== NANOG may be useful in the [[immunohistochemical]] diagnosis of tumors. NANOG is expressed in [[germ cell]]s of the [[fetus]] and in some [[germ cell tumor]]s of the [[gonads]]<ref> Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E. Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. Histopathology. 2005 Jul;47(1):48-56. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=15982323&query_hl=28&itool=pubmed_docsum PubMed]</ref> and [[central nervous system]] (CNS).<ref name=Santagata>Santagata S, Hornick JL, Ligon KL. Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG. Am J Surg Pathol. 2006 Dec;30(12):1613-8. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=17122519&query_hl=28&itool=pubmed_docsum PubMed]</ref> Among germ cell tumors, NANOG is expressed by [[seminoma]] and [[embryonal carcinoma]] but not by [[teratoma|mature teratoma]] nor [[endodermal sinus tumor]]<ref> Hart AH, Hartley L, Parker K, Ibrahim M, Looijenga LH, Pauchnik M, Chow CW, Robb L. The pluripotency homeobox gene NANOG is expressed in human germ cell tumors. Cancer. 2005 Nov 15;104(10):2092-8. [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&dopt=AbstractPlus&list_uids=16206293&query_hl=28&itool=pubmed_docsum PubMed]</ref>; expression of NANOG by [[teratoma|immature teratoma]] and [[choriocarcinoma]] is unknown. Among tumors usually found in the CNS, NANOG is expressed by [[germinoma]] (a germ cell tumor histologically identical to [[seminoma]] and [[dysgerminoma]]) but not by [[pineoblastoma]], [[lymphoma]], [[pituitary adenoma]] and [[glioma]]s;<ref name=Santagata/> expression of NANOG by other germ cell tumors of the CNS is unknown. ===Evolutionary biology=== [[Human]]s and [[chimpanzee]]s share ten NANOG [[pseudogene]]s, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the [[Polyadenylation|poly-(A) tail]]s characteristic of most retropseudogenes, indicating copying errors occurred during their creation. Due to the high improbability that the same pseudogenes (copying errors included) would exist in the same places in two unrelated [[genome]]s, [[Evolutionary biology|evolutionary biologists]] point to NANOG and its pseudogenes as providing formidable [[evidence of common descent]] between humans and chimpazees.<ref>Daniel J. Fairbanks, ''Relics of Eden'' (Amherst, New York: Prometheus Books 2007), pp. 94-96, 177-182.</ref> ==See also== *[[Enhancer]] *[[Histone]] *[[Oct-4]] *[[Pribnow box]] *[[Promoter]] *[[RNA polymerase]] *[[Brachyury]] *[[Transcription factors]] *[[Gene regulatory network]] *[[Bioinformatics]] *[[PubMed|NANOG]] ==Sources== *[http://www.nytimes.com/2005/09/13/health/13cell.html New York Times] "He has now applied the technique to human cells, starting with embryonic stem cells. The cells, he and colleagues say in the current issue of Cell, are controlled by a triumvirate of three transcription factors, known as '''oct4, sox2 and nanog'''. *[http://www.wi.mit.edu/research/summaries/jaenisch.html MIT] "The transcription factors Oct4, Sox2, and Nanog have essential roles in early development and are required for the propagation of undifferentiated embryonic stem (ES) cells in culture. To gain insights into transcriptional regulation of human ES cells, we have, in collaboration with the Young lab, identified Oct4, Sox2, and Nanog target genes using genome-scale location analysis. We found, surprisingly, that Oct4, Sox2, and Nanog co-occupy a substantial portion of their target genes. These target genes frequently encode transcription factors, many of which are developmentally important homeodomain proteins. Our data also show that Oct4, Sox2, and Nanog collaborate to form regulatory circuitry in ES cells consisting of autoregulatory and feedforward loops." *[http://jura.wi.mit.edu/young_public/hESregulation/index.html Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells] * Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S and Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell May 30;113(5):643-55 (2003). * Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M and Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell May 30;113(5):631-42 (2003) * Lin TX, Chao C, Saito S, et al. P53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression. NATURE CELL BIOLOGY 7 (2): 165-U80 FEB 2005. ==External links== * {{MeshName|NANOG+protein,+human}} * {{MeshName|Nanog+protein,+mouse}} ==References== {{Reflist|2}} ==Further reading== {{refbegin | 2}} {{PBB_Further_reading | citations = *{{cite journal | author=Cavaleri F, Schöler HR |title=Nanog: a new recruit to the embryonic stem cell orchestra. |journal=Cell |volume=113 |issue= 5 |pages= 551–2 |year= 2003 |pmid= 12787492 |doi= }} *{{cite journal | author=Constantinescu S |title=Stemness, fusion and renewal of hematopoietic and embryonic stem cells. |journal=J. Cell. Mol. Med. |volume=7 |issue= 2 |pages= 103–12 |year= 2004 |pmid= 12927049 |doi= }} *{{cite journal | author=Pan G, Thomson JA |title=Nanog and transcriptional networks in embryonic stem cell pluripotency. |journal=Cell Res. |volume=17 |issue= 1 |pages= 42–9 |year= 2007 |pmid= 17211451 |doi= 10.1038/sj.cr.7310125 }} *{{cite journal | author=Mitsui K, Tokuzawa Y, Itoh H, ''et al.'' |title=The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. |journal=Cell |volume=113 |issue= 5 |pages= 631–42 |year= 2003 |pmid= 12787504 |doi= }} *{{cite journal | author=Chambers I, Colby D, Robertson M, ''et al.'' |title=Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. |journal=Cell |volume=113 |issue= 5 |pages= 643–55 |year= 2003 |pmid= 12787505 |doi= }} *{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40–5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }} *{{cite journal | author=Clark AT, Rodriguez RT, Bodnar MS, ''et al.'' |title=Human STELLAR, NANOG, and GDF3 genes are expressed in pluripotent cells and map to chromosome 12p13, a hotspot for teratocarcinoma. |journal=Stem Cells |volume=22 |issue= 2 |pages= 169–79 |year= 2004 |pmid= 14990856 |doi= }} *{{cite journal | author=Hart AH, Hartley L, Ibrahim M, Robb L |title=Identification, cloning and expression analysis of the pluripotency promoting Nanog genes in mouse and human. |journal=Dev. Dyn. |volume=230 |issue= 1 |pages= 187–98 |year= 2004 |pmid= 15108323 |doi= 10.1002/dvdy.20034 }} *{{cite journal | author=Booth HA, Holland PW |title=Eleven daughters of NANOG. |journal=Genomics |volume=84 |issue= 2 |pages= 229–38 |year= 2005 |pmid= 15233988 |doi= 10.1016/j.ygeno.2004.02.014 }} *{{cite journal | author=Hatano SY, Tada M, Kimura H, ''et al.'' |title=Pluripotential competence of cells associated with Nanog activity. |journal=Mech. Dev. |volume=122 |issue= 1 |pages= 67–79 |year= 2005 |pmid= 15582778 |doi= 10.1016/j.mod.2004.08.008 }} *{{cite journal | author=Deb-Rinker P, Ly D, Jezierski A, ''et al.'' |title=Sequential DNA methylation of the Nanog and Oct-4 upstream regions in human NT2 cells during neuronal differentiation. |journal=J. Biol. Chem. |volume=280 |issue= 8 |pages= 6257–60 |year= 2005 |pmid= 15615706 |doi= 10.1074/jbc.C400479200 }} *{{cite journal | author=Zaehres H, Lensch MW, Daheron L, ''et al.'' |title=High-efficiency RNA interference in human embryonic stem cells. |journal=Stem Cells |volume=23 |issue= 3 |pages= 299–305 |year= 2005 |pmid= 15749924 |doi= 10.1634/stemcells.2004-0252 }} *{{cite journal | author=Hoei-Hansen CE, Almstrup K, Nielsen JE, ''et al.'' |title=Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours. |journal=Histopathology |volume=47 |issue= 1 |pages= 48–56 |year= 2005 |pmid= 15982323 |doi= 10.1111/j.1365-2559.2005.02182.x }} *{{cite journal | author=Hyslop L, Stojkovic M, Armstrong L, ''et al.'' |title=Downregulation of NANOG induces differentiation of human embryonic stem cells to extraembryonic lineages. |journal=Stem Cells |volume=23 |issue= 8 |pages= 1035–43 |year= 2006 |pmid= 15983365 |doi= 10.1634/stemcells.2005-0080 }} *{{cite journal | author=Oh JH, Do HJ, Yang HM, ''et al.'' |title=Identification of a putative transactivation domain in human Nanog. |journal=Exp. Mol. Med. |volume=37 |issue= 3 |pages= 250–4 |year= 2005 |pmid= 16000880 |doi= }} *{{cite journal | author=Boyer LA, Lee TI, Cole MF, ''et al.'' |title=Core transcriptional regulatory circuitry in human embryonic stem cells. |journal=Cell |volume=122 |issue= 6 |pages= 947–56 |year= 2005 |pmid= 16153702 |doi= 10.1016/j.cell.2005.08.020 }} *{{cite journal | author=Kim JS, Kim J, Kim BS, ''et al.'' |title=Identification and functional characterization of an alternative splice variant within the fourth exon of human nanog. |journal=Exp. Mol. Med. |volume=37 |issue= 6 |pages= 601–7 |year= 2006 |pmid= 16391521 |doi= }} *{{cite journal | author=Darr H, Mayshar Y, Benvenisty N |title=Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features. |journal=Development |volume=133 |issue= 6 |pages= 1193–201 |year= 2006 |pmid= 16501172 |doi= 10.1242/dev.02286 }} }} {{refend}} {{Transcription factors|g3}} [[Category:Gene expression]] [[Category:Genes]] [[Category:Oncology]] [[Category:Transcription factors]] [[cs:Nanog]] [[sk:Nanog]] <!-- The PBB_Controls template provides controls for Protein Box Bot, please see Template:PBB_Controls for details. --> {{PBB_Controls | update_page = yes | require_manual_inspection = no | update_protein_box = yes | update_summary = yes | update_citations = yes }}