Biology:Homeobox protein NANOG

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Short description: Mammalian protein found in humans


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

Homeobox protein NANOG (hNanog) is a transcriptional factor that helps embryonic stem cells (ESCs) maintain pluripotency by suppressing cell determination factors.[1] hNanog is encoded in humans by the NANOG gene. Several types of cancer are associated with NANOG.[2]

Etymology

The name NANOG derives from Tír na nÓg (Irish for "Land of the Young"), a name given to the Celtic Otherworld in Irish and Scottish mythology.[3][4]

Structure

The human hNanog protein coded by the NANOG gene, consists of 305 amino acids and possesses 3 functional domains: the N-terminal domain, the C- terminal domain, and the conserved homeodomain motif. The homeodomain region facilitates DNA binding. The NANOG is located on chromosome 12, and the mRNA contains a 915 bp open reading frame (ORF) with 4 exons and 3 introns.[4]

The N-terminal region of hNanog is rich in serine, threonine and proline residues, and the C-terminus contains a tryptophan-rich domain. The homeodomain in hNANOG ranges from residues 95 to 155. There are also additional NANOG genes (NANOG2, NANOG p8) which potentially affect ESCs' differentiation. Scientists have shown that NANOG is fundamental for self-renewal and pluripotency, and NANOG p8 is highly expressed in cancer cells.[5]

Function

Transcription programs in embryonic stem cells

NANOG is a transcription factor 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 (Oct-4) 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.

NANOG has been described to be expressed in the posterior side of the epiblast at the onset of gastrulation.[6] There, NANOG has been implicated in inhibiting embryonic hematopoiesis by repressing the expression of the transcription factor Tal1.[7] In this embryonic stage, NANOG represses Pou3f1, a transcription factor crucial for the anterior-posterior axis formation.[6]

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.[8]

POU5F1, TDGF1 (CRIPTO), SALL4, LECT1, and BUB1 are also related genes all responsible for self-renewal and pluripotent differentiation.[9]

The NANOG protein has been found to be a transcriptional activator for the Rex1 promoter, playing a key role in sustaining Rex1 expression. Knockdown of NANOG in embryonic stem cells results in a reduction of Rex1 expression, while forced expression of NANOG stimulates Rex1 expression.[10]

Besides the effects of NANOG in the embryonic stages of life, ectopic expression of NANOG in the adult stem cells can restore the proliferation and differentiation potential that is lost due to organismal aging or cellular senescence.[11][12][13][14][15]

Clinical significance

Cancer

NANOG is highly expressed in cancer stem cells and may thus function as an oncogene to promote carcinogenesis. High expression of NANOG correlates with poor survival in cancer patients.[16][17][18]

Recent research has shown that the localization of NANOG and other transcription factors have potential consequences on cellular function. Experimental evidence has shown that the level of NANOG p8 expression is elevated specially in cancer cells, which mean that NANOG p8 gene is a critical member in (CSCs) Cancer stem cells, so knocking it down could reduce the cancer malignancy.[5]

Diagnostics

NANOG p8 gene has been evaluated as a prognostic and predictive cancer biomarker.[19]

Cancer stem cells

Nanog is a transcription factor that controls both self-renewal and pluripotency of embryonic stem cells. Similarly, the expression of Nanog family proteins is increased in many types of cancer and correlates with a worse prognosis.[5]

Evolution

Humans and chimpanzees share ten NANOG pseudogenes (NanogP2-P11) during evaluation, two of them are located on the X chromosome and they characterized by the 5’ promoter sequences and the absence of introns as a result of mRNA retrotransposition[4] 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 that 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 evidence of common descent between humans and chimpanzees.[20]

See also

References

  1. ↑ Heurtier, V., Owens, N., Gonzalez, I. et al. The molecular logic of Nanog-induced self-renewal in mouse embryonic stem cells. Nat Commun 10, 1109 (2019). https://doi.org/10.1038/s41467-019-09041-z
  2. ↑ "NANOG expression in human development and cancerogenesis". Experimental Biology and Medicine 245 (5): 456–464. March 2020. doi:10.1177/1535370220905560. PMID 32041418. 
  3. ↑ "ScienceDaily: Cells Of The Ever Young: Getting Closer To The Truth". https://www.sciencedaily.com/releases/2003/06/030602024530.htm. 
  4. ↑ 4.0 4.1 4.2 "The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells". Cancer Biology & Therapy 17 (1): 1–10. 2015-11-30. doi:10.1080/15384047.2015.1121348. PMID 26618281. 
  5. ↑ 5.0 5.1 5.2 "Insights into the Nanog gene: A propeller for stemness in primitive stem cells". International Journal of Biological Sciences 12 (11): 1372–1381. 2016. doi:10.7150/ijbs.16349. PMID 27877089. 
  6. ↑ 6.0 6.1 "Nanog regulates Pou3f1 expression at the exit from pluripotency during gastrulation". Biology Open 8 (11): bio046367. December 2019. doi:10.1242/bio.046367. PMID 31791948. 
  7. ↑ "The pluripotency factor NANOG controls primitive hematopoiesis and directly regulates Tal1". The EMBO Journal 38 (7). April 2019. doi:10.15252/embj.201899122. PMID 30814124. 
  8. ↑ "Derivation of human embryonic stem cells from developing and arrested embryos". Stem Cells 24 (12): 2669–2676. December 2006. doi:10.1634/stemcells.2006-0377. PMID 16990582. 
  9. ↑ "Characterization and gene expression profiling of five new human embryonic stem cell lines derived in Taiwan". Stem Cells and Development 15 (4): 532–555. August 2006. doi:10.1089/scd.2006.15.532. PMID 16978057. 
  10. ↑ "Regulation of the pluripotency marker Rex-1 by Nanog and Sox2". The Journal of Biological Chemistry 281 (33): 23319–23325. August 2006. doi:10.1074/jbc.M601811200. PMID 16714766. 
  11. ↑ "NANOG restores the impaired myogenic differentiation potential of skeletal myoblasts after multiple population doublings". Stem Cell Research 26: 55–66. January 2018. doi:10.1016/j.scr.2017.11.018. PMID 29245050. 
  12. ↑ "NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues". Tissue Engineering. Part A 23 (11–12): 535–545. June 2017. doi:10.1089/ten.TEA.2016.0494. PMID 28125933. 
  13. ↑ "NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression". Stem Cells 35 (1): 207–221. January 2017. doi:10.1002/stem.2452. PMID 27350449. 
  14. ↑ "Nanog reverses the effects of organismal aging on mesenchymal stem cell proliferation and myogenic differentiation potential". Stem Cells 30 (12): 2746–2759. December 2012. doi:10.1002/stem.1223. PMID 22949105. 
  15. ↑ "Nanog induces suppression of senescence through downregulation of p27KIP1 expression". Journal of Cell Science 129 (5): 912–920. March 2016. doi:10.1242/jcs.167932. PMID 26795560. 
  16. ↑ "Regulation of NANOG in cancer cells". Molecular Carcinogenesis 54 (9): 679–687. September 2015. doi:10.1002/mc.22340. PMID 26013997. 
  17. ↑ "Concise Review: NANOG in Cancer Stem Cells and Tumor Development: An Update and Outstanding Questions". Stem Cells 33 (8): 2381–2390. August 2015. doi:10.1002/stem.2007. PMID 25821200. 
  18. ↑ "The role of NANOG transcriptional factor in the development of malignant phenotype of cancer cells". Cancer Biology & Therapy 17 (1): 1–10. 2016. doi:10.1080/15384047.2015.1121348. PMID 26618281. 
  19. ↑ "Emerging role of nanog in tumorigenesis and cancer stem cells". International Journal of Cancer 135 (12): 2741–2748. December 2014. doi:10.1002/ijc.28690. PMID 24375318. 
  20. ↑ Relics of Eden: The Powerful Evidence of Evolution in Human DNA. Buffalo, N.Y: Prometheus Books. 2007. pp. 94–96, 177–182. ISBN 978-1-59102-564-1. 

Further reading

External links



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