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Oct-4

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For the day, see October 4.
"Oct-3" redirects here. For the day, see October 3.

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Oct-4 (octamer-binding transcription factor 4) also known as POU5F1 (POU domain, class 5, transcription factor 1) is a protein that in humans is encoded by the POU5F1 gene.[1] Oct-4 is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells.[2] As such, it is frequently used as a marker for undifferentiated cells. Oct-4 expression must be closely regulated; too much or too little will cause differentiation of the cells.[3]

The octamer (made of eight units) in this family of transcription factors is the DNA nucleotide sequence "ATTTGCAT", the etymology for the naming of the octamer transcription factor.[4]

Expression and function

Oct-4 transcription factor is initially active as a maternal factor in the oocyte but remains active in embryos throughout the preimplantation period. Oct-4 expression is associated with an undifferentiated phenotype and tumors.[5] Gene knockdown of Oct-4 promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[6] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[7]

Mouse embryos that are Oct-4-deficient or have low expression levels of Oct-4 fail to form the inner cell mass, lose pluripotency and differentiate into trophectoderm. Therefore, the level of Oct-4 expression in mice is vital for regulating pluripotency and early cell differentiation since one of its main functions is to keep the embryo from differentiating.

Orthologs

Orthologs of Oct-4 exist in humans and several other species including:

Species Entrez GeneID Chromosome Location RefSeq (mRNA) RefSeq (protein)
Mus musculus 18999 17,17 B1; 17 19.23 cM NC_000083.4, 35114104..35118822 (Plus Strand) NM_013633.1 NP_038661.1
Homo sapiens 5460 6, 6p21.31 NC_000006.10, 31246432-31240107 (Minus Strand) NM_002701.3 NP_002692.2 (full length isoform)
NP_002692.1 (N-terminal truncated isoform)
Rattus norvegicus 294562 20 NW_001084776, 650467-655015 (Minus strand) NM_001009178 NP_001009178
Danio rerio (Zebrafish) 303333 21 NC_007127.1, 27995548-28000317 (Minus strand) NM_131112 NP_571187

Structural Information

Oct-4 contains the following protein domains:

Domain Description Length (AA)
POU domain Found in Pit-Oct-Unc transcription factors 75
Homeodomain DNA binding domains involved in the transcriptional regulation of key eukaryotic developmental processes; may bind to DNA as monomers or as homo- and/or heterodimers, in a sequence-specific manner. 59

Implications in disease

Oct-4 has been implicated in tumorigenesis of adult germ cells. Ectopic expression of the factor in adult mice has been found to cause the formation of dysplastic lesions of the skin and intestine. The intestinal dysplasia resulted from an increase in progenitor cell population and the upregulation of β-catenin transcription through the inhibition of cellular differentiation.[8]

Pluripotency in embryo development

Animal model

In 2000, Niwa et al. used conditional expression and repression in murine embryonic stem (ES) cells to determine requirements for Oct-4 in the maintenance of developmental potency.[3] Although transcriptional determination has usually been considered as a binary on-off control system, they found that the precise level of Oct-4 governs 3 distinct fates of ES cells. A less-than-2-fold increase in expression causes differentiation into primitive endoderm and mesoderm. In contrast, repression of Oct-4 induces loss of pluripotency and dedifferentiation to trophectoderm. Thus, a critical amount of Oct-4 is required to sustain stem cell self-renewal, and up- or down regulation induces divergent developmental programs. Niwa et al. suggested that their findings established a role for Oct-4 as a master regulator of pluripotency that controls lineage commitment and illustrated the sophistication of critical transcriptional regulators and the consequent importance of quantitative analyzes.

The transcription factors Oct-4, Sox2 and Nanog are capable of inducing the expression of each other, and are essential for maintaining the self-renewing undifferentiated state of the inner cell mass of the blastocyst, as well as in embryonic stem cells (which are cell lines derived from the inner cell mass).[7]

Oct-4 is one of the transcription factors used to create induced pluripotent stem cells, together with Sox2, Klf4 and often c-Myc in mouse,[9][10][11] demonstrating its capacity to induce an embryonic stem cell-like state. It was later deterimined that only two of these four factors, Oct4 and Klf4 were sufficient to reprogram mouse adult neural stem cells.[12] Finally it was shown that a single factor, Oct-4 was sufficient for this transformation.[13]

In embryonic stem cells

In in-vitro experiments of murine Embryonic Stem Cells, Oct-4 has often been used as a marker of stemness, as differentiated cells show reduced expression of this marker.

Oct3/4 can both repress and activate the Rex1 promoter. In cells that already express high level of Oct3/4, exogenously transfected Oct3/4 will lead to the repression of Rex1.[14] However, in cells that are not actively expressing Oct3/4, an exogenous transfection of Oct3/4 will lead to the activation of Rex1.[14] This implies a dual regulatory ability of Oct3/4 on Rex1. At low levels of the Oct3/4 protein, the Rex1 promoter is activated, while at high levels of the Oct3/4 protein, the Rex1 promoter is repressed.

In adult stem cells

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from epithelium, bone marrow, liver, etc.).[15] Other scientists have produced evidence to the contrary,[16] and dismiss those studies as artifacts of in vitro culture, or interpreting background noise as signal,[17] and warn about Oct-4 pseudogenes giving false detection of Oct-4 expression.[18] Oct-4 has also been implicated as a marker of cancer stem cells.[19][20]

See also

References

  1. ^ Takeda J, Seino S, Bell GI (Sep 1992). "Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues". Nucleic Acids Research. 20 (17): 4613–20. doi:10.1093/nar/20.17.4613. PMC 334192. PMID 1408763.
  2. ^ Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells at MIT
  3. ^ a b Niwa H, Miyazaki J, Smith AG (Apr 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nature Genetics. 24 (4): 372–6. doi:10.1038/74199. PMID 10742100.
  4. ^ Petryniak B, Staudt LM, Postema CE, McCormack WT, Thompson CB (Feb 1990). "Characterization of chicken octamer-binding proteins demonstrates that POU domain-containing homeobox transcription factors have been highly conserved during vertebrate evolution". Proceedings of the National Academy of Sciences of the United States of America. 87 (3): 1099–103. doi:10.1073/pnas.87.3.1099. PMC 53418. PMID 1967834.
  5. ^ Looijenga LH, Stoop H, de Leeuw HP, de Gouveia Brazao CA, Gillis AJ, van Roozendaal KE, van Zoelen EJ, Weber RF, Wolffenbuttel KP, van Dekken H, Honecker F, Bokemeyer C, Perlman EJ, Schneider DT, Kononen J, Sauter G, Oosterhuis JW (May 2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Research. 63 (9): 2244–50. PMID 12727846.
  6. ^ Zaehres H, Lensch MW, Daheron L, Stewart SA, Itskovitz-Eldor J, Daley GQ (Mar 2005). "High-efficiency RNA interference in human embryonic stem cells". Stem Cells. 23 (3): 299–305. doi:10.1634/stemcells.2004-0252. PMID 15749924.
  7. ^ a b Rodda DJ, Chew JL, Lim LH, Loh YH, Wang B, Ng HH, Robson P (Jul 2005). "Transcriptional regulation of nanog by OCT4 and SOX2". The Journal of Biological Chemistry. 280 (26): 24731–7. doi:10.1074/jbc.M502573200. PMID 15860457.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  8. ^ Hochedlinger K, Yamada Y, Beard C, Jaenisch R (May 2005). "Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues". Cell. 121 (3): 465–77. doi:10.1016/j.cell.2005.02.018. PMID 15882627.
  9. ^ Okita K, Ichisaka T, Yamanaka S (Jul 2007). "Generation of germline-competent induced pluripotent stem cells". Nature. 448 (7151): 313–7. doi:10.1038/nature05934. PMID 17554338.
  10. ^ Wernig M, Meissner A, Foreman R, Brambrink T, Ku M, Hochedlinger K, Bernstein BE, Jaenisch R (Jul 2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature. 448 (7151): 318–24. doi:10.1038/nature05944. PMID 17554336.
  11. ^ Maherali N, Sridharan R, Xie W, Utikal J, Eminli S, Arnold K, Stadtfeld M, Yachechko R, Tchieu J, Jaenisch R, Plath K, Hochedlinger K (Jun 2007). "Directly reprogrammed fibroblasts show global epigenetic remodeling and widespread tissue contribution". Cell Stem Cell. 1 (1): 55–70. doi:10.1016/j.stem.2007.05.014. PMID 18371336.
  12. ^ Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR (Jul 2008). "Pluripotent stem cells induced from adult neural stem cells by reprogramming with two factors". Nature. 454 (7204): 646–50. doi:10.1038/nature07061. PMID 18594515.
  13. ^ Kim JB, Sebastiano V, Wu G, Araúzo-Bravo MJ, Sasse P, Gentile L, Ko K, Ruau D, Ehrich M, van den Boom D, Meyer J, Hübner K, Bernemann C, Ortmeier C, Zenke M, Fleischmann BK, Zaehres H, Schöler HR (Feb 2009). "Oct4-induced pluripotency in adult neural stem cells". Cell. 136 (3): 411–9. doi:10.1016/j.cell.2009.01.023. PMID 19203577.
  14. ^ a b Ben-Shushan E, Thompson JR, Gudas LJ, Bergman Y (Apr 1998). "Rex-1, a gene encoding a transcription factor expressed in the early embryo, is regulated via Oct-3/4 and Oct-6 binding to an octamer site and a novel protein, Rox-1, binding to an adjacent site". Molecular and Cellular Biology. 18 (4): 1866–78. PMC 121416. PMID 9528758.
  15. ^ For example:
  16. ^ Lengner CJ, Camargo FD, Hochedlinger K, Welstead GG, Zaidi S, Gokhale S, Scholer HR, Tomilin A, Jaenisch R (Oct 2007). "Oct4 expression is not required for mouse somatic stem cell self-renewal". Cell Stem Cell. 1 (4): 403–15. doi:10.1016/j.stem.2007.07.020. PMC 2151746. PMID 18159219.
  17. ^ Lengner CJ, Welstead GG, Jaenisch R (Mar 2008). "The pluripotency regulator Oct4: a role in somatic stem cells?". Cell Cycle. 7 (6): 725–8. doi:10.4161/cc.7.6.5573. PMID 18239456.
  18. ^ Zangrossi S, Marabese M, Broggini M, Giordano R, D'Erasmo M, Montelatici E, Intini D, Neri A, Pesce M, Rebulla P, Lazzari L (Jul 2007). "Oct-4 expression in adult human differentiated cells challenges its role as a pure stem cell marker". Stem Cells. 25 (7): 1675–80. doi:10.1634/stemcells.2006-0611. PMID 17379765.
  19. ^ Kim RJ, Nam JS (Jun 2011). "OCT4 Expression Enhances Features of Cancer Stem Cells in a Mouse Model of Breast Cancer". Laboratory Animal Research. 27 (2): 147–52. doi:10.5625/lar.2011.27.2.147. PMC 3145994. PMID 21826175.
  20. ^ Atlasi Y, Mowla SJ, Ziaee SA, Bahrami AR (Apr 2007). "OCT-4, an embryonic stem cell marker, is highly expressed in bladder cancer". International Journal of Cancer. Journal International Du Cancer. 120 (7): 1598–602. doi:10.1002/ijc.22508. PMID 17205510.

Further reading

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