Homeobox protein NANOG

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See NANOG (computing) for the network operators' group.

Template:PBB NANOG (pron. nanOg) is a transcription factor critically involved with self-renewal of undifferentiated embryonic stem cells. In humans, this protein is encoded by the NANOG gene.[1][2]

Structure

Human NANOG protein is a 305 amino acid protein with a conserved homeodomain motif that is localized to the nuclear component of cells. The homeodomain which 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 95 to 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.

Function

NANOG is a gene expressed in embryonic stem cells (ESCs) and is thought to be a key factor in maintaining pluripotency. NANOG is thought to function in concert with other factors such as 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.

Analysis of arrested embryos demonstrated that embryos express pluripotency marker genes such as POU5F1, 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.[3]

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[4]

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.[1][2]

Loss of Nanog function causes differentiation of embryonic stem cells into other cell types.[5]

NANOG overexpression in human embryonic stem cells enables their propagation for multiple passages during which the cells remain pluripotent.[6] Gene knockdown of Nanog promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[7]

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 embryonic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis.[5]

Nanog transforms 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.[8]

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.[9]

Yamanaka et al., demonstrate 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.[10]

Clinical medicine

NANOG may be useful in the immunohistochemical diagnosis of tumors. NANOG is expressed in germ cells of the fetus and in some germ cell tumors of the gonads[11] and central nervous system (CNS).[12][13] Expression of NANOG by 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 gliomas;[12] expression of NANOG by other germ cell tumors of the CNS is unknown.

Evolutionary biology

Humans and chimpanzees share ten NANOG pseudogenes, all in the same places: one duplication pseudogene and nine retropseudogenes. Of the nine shared NANOG retropseudogenes, two lack the poly-(A) tails 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 genomes, evolutionary biologists point to NANOG and its pseudogenes as providing formidable evidence of common descent between humans and chimpazees.[14]

Discovery

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 nOg legend."[15]

See also

References

  1. ^ a b Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S (2003). "The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells". Cell. 113 (5): 631–42. doi:10.1016/S0092-8674(03)00393-3. PMID 12787504. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  2. ^ a b Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A (2003). "Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells". Cell. 113 (5): 643–55. doi:10.1016/S0092-8674(03)00392-1. PMID 12787505. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  3. ^ Zhang X, Stojkovic P, Przyborski S, Cooke M, Armstrong L, Lako M, Stojkovic M (2006). "Derivation of human embryonic stem cells from developing and arrested embryos". Stem Cells. 24 (12): 2669–76. doi:10.1634/stemcells.2006-0377. PMID 16990582. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  4. ^ Li SS, Liu YH, Tseng CN, Chung TL, Lee TY, Singh S (2006). "Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan". Stem Cells Dev. 15 (4): 532–55. doi:10.1089/scd.2006.15.532. PMID 16978057. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  5. ^ a b Lin T, Chao C, Saito S, Mazur SJ, Murphy ME, Appella E, Xu Y (2005). "p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression". Nat. Cell Biol. 7 (2): 165–71. doi:10.1038/ncb1211. PMID 15619621. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  6. ^ Darr H, Mayshar Y, Benvenisty N (2006). "Overexpression of NANOG in human ES cells enables feeder-free growth while inducing primitive ectoderm features". Development. 133 (6): 1193–201. doi:10.1242/dev.02286. PMID 16501172. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  7. ^ Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells. 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Piestun D, Kochupurakkal BS, Jacob-Hirsch J, Zeligson S, Koudritsky M, Domany E, Amariglio N, Rechavi G, Givol D (2006). "Nanog transforms NIH3T3 cells and targets cell-type restricted genes". Biochem. Biophys. Res. Commun. 343 (1): 279–85. doi:10.1016/j.bbrc.2006.02.152. PMID 16540082. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  9. ^ Yates A, Chambers I (2005). "The homeodomain protein Nanog and pluripotency in mouse embryonic stem cells". Biochem. Soc. Trans. 33 (Pt 6): 1518–21. doi:10.1042/BST20051518. PMID 16246159. {{cite journal}}: Unknown parameter |month= ignored (help)
  10. ^ Takahashi K, Yamanaka S (2006). "Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors". Cell. 126 (4): 663–76. doi:10.1016/j.cell.2006.07.024. PMID 16904174. {{cite journal}}: Unknown parameter |month= ignored (help)
  11. ^ Hoei-Hansen CE, Almstrup K, Nielsen JE, Brask Sonne S, Graem N, Skakkebaek NE, Leffers H, Rajpert-De Meyts E (2005). "Stem cell pluripotency factor NANOG is expressed in human fetal gonocytes, testicular carcinoma in situ and germ cell tumours". Histopathology. 47 (1): 48–56. doi:10.1111/j.1365-2559.2005.02182.x. PMID 15982323. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ a b Santagata S, Hornick JL, Ligon KL (2006). "Comparative analysis of germ cell transcription factors in CNS germinoma reveals diagnostic utility of NANOG". Am. J. Surg. Pathol. 30 (12): 1613–8. doi:10.1097/01.pas.0000213320.04919.1a. PMID 17122519. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Hart AH, Hartley L, Parker K, Ibrahim M, Looijenga LH, Pauchnik M, Chow CW, Robb L (2005). "The pluripotency homeobox gene NANOG is expressed in human germ cell tumors". Cancer. 104 (10): 2092–8. doi:10.1002/cncr.21435. PMID 16206293. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  14. ^ Daniel J. Fairbanks (2007). Relics of Eden: The Powerful Evidence of Evolution in Human DNA. Buffalo, N.Y: Prometheus Books. pp. 94–96, 177–182. ISBN 1-59102-564-8.
  15. ^ "ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth". Retrieved 2007-07-26.

Further reading

Template:PBB Further reading

External links

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