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POU domain, class 5, transcription factor 1
Identifiers
Symbols POU5F1; MGC22487; OCT3; OCT4; OTF3; OTF4
External IDs OMIM164177 MGI101893 HomoloGene8422 GeneCards: POU5F1 Gene
RNA expression pattern
PBB GE POU5F1 210265 x at tn.png
PBB GE POU5F1 208286 x at tn.png
PBB GE POU5F1 210905 x at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5460 18999
Ensembl ENSG00000204531 ENSMUSG00000024406
UniProt Q01860 n/a
RefSeq (mRNA) NM_002701 NM_013633
RefSeq (protein) NP_002692 NP_038661
Location (UCSC) Chr 6:
31.24 - 31.25 Mb
Chr 17:
35.11 - 35.12 Mb
PubMed search [1] [2]

Oct-4 (an abbreviation of Octamer-4) is a commonly used synonym for POU5F1 (POU class 5 homeobox 1). It is a homeodomain transcription factor of the POU family. This protein is critically involved in the self-renewal of undifferentiated embryonic stem cells.[1] 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 actually cause differentiation of the cells.[2]

Contents

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.[3] In fact gene knockdown of Oct-4 promotes differentiation, thereby demonstrating a role for these factors in human embryonic stem cell self-renewal.[4] Oct-4 can form a heterodimer with Sox2, so that these two proteins bind DNA together.[5]

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.

NCBI Information

Species Genetics Location
Mus musculus GeneID: 18999, refseq for the protein: NP_038661.1, refseq for mRNA: NM_013633.1 Genomic Location: NC_000083.4, 35114104..35118822 (Plus Strand). Chromosome: 17,17 B1; 17 19.23 cM
Homo sapiens GeneID: 5460, refseq for the protein: NP_002692.2, refseq for mRNA: NM_002701.3. There are two different isoforms for OCT4 in human, the insoform #2 looks like a N terminal truncation or the #1 [3]. Genomic Location: NC_000006.10, 31246432-31240107 (Minus Strand). Chromosome: 6, 6p21.31
Rattus norvegicus GeneID: 294562, refseq for the protein: NP_001009178, refseq for mRNA: NM_001009178 Genomic Location: NW_001084776, 650467-655015 (Minus strand). Chromosome: 20.
Danio rerio GeneID: 303333, refseq for the protein: NP_571187, reseq for mRNA: NM_131112 Genomic Location: NC_007127.1, 27995548-28000317 (Minus strand). Chromosome: 21.

Different alignment methods will give the different results about the orthologs. there are other orthologs from Drosophila(NCBI-GeneID: 38752[4]),C.elegans(NCBI-GeneID: 172640[5]) and so on. The two proteins are important in the development of animals.

Structural Information

Conserved Domain
conserved domain POU[6] homeodomain[7]
Length 75aa 59aa
Description Found in Pit-Oct-Unc transcription factors 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.

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]

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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.[2] 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).[5]

Oct-4 is 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]

Several studies suggest a role for Oct-4 in sustaining self-renewal capacity of adult somatic stem cells (i.e. stem cells from intestinal epithelium, bone marrow, retina, brain, liver, etc.). However, Rudolf Jaenisch's group in Oct 2007 contradicted this hypothesis by documenting no role of Oct-4 in mouse somatic stem cell self-renewal.[14]

See also

References

  1. ^ Young Lab- Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells at MIT
  2. ^ a b Niwa H, Miyazaki J, Smith AG (April 2000). "Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells". Nat. Genet. 24 (4): 372–6. doi:10.1038/74199. PMID 10742100.  
  3. ^ Looijenga LH, Stoop H, de Leeuw HP, et al. (2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Res. 63 (9): 2244–50. PMID 12727846.  
  4. ^ 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.  
  5. ^ a b Rodda DJ, Chew JL, Lim LH, et al. (July 2005). "Transcriptional regulation of nanog by OCT4 and SOX2". J. Biol. Chem. 280 (26): 24731–7. doi:10.1074/jbc.M502573200. PMID 15860457. http://www.jbc.org/cgi/content/full/280/26/24731.  
  6. ^ "NCBI CDD smart00352". http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=smart00352&version=v2.09. Retrieved 2007-06-20.  
  7. ^ "NCBI CDD cd00086". http://www.ncbi.nlm.nih.gov/Structure/cdd/cddsrv.cgi?uid=cd00086. Retrieved 2007-06-20.  
  8. ^ Hochedlinger K, Yamada Y, Beard C, Jaenisch R (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, Keisuke; Ichisaka, Tomoko; Yamanaka, Shinya (2007). "Generation of germline-competent induced pluripotent stem cells". Nature 448 (7151): 313–317. doi:10.1038/nature05934. PMID 17554338.  
  10. ^ Wernig, Marius; et al. (2007). "In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state". Nature 448 (7151): 318–324. doi:10.1038/nature05944. PMID 17554336.  
  11. ^ Maherali, N.; et al. (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.  
  12. ^ Kim JB, Zaehres H, Wu G, Gentile L, Ko K, Sebastiano V, Araúzo-Bravo MJ, Ruau D, Han DW, Zenke M, Schöler HR (July 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 M, Schöler HR (February 2009). "Oct4-Induced Pluripotency in Adult Neural Stem Cells". Cell 136 (3): 411–419. doi:10.1016/j.cell.2009.01.023.  
  14. ^ Lengner CJ, Camargo FD, Hochedlinger K, et al. (October 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. PMID 18159219.  

Further reading

  • Lamoury F, Croitoru-Lamoury J, Brew B (2006). "Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1". Cytotherapy 8 (3): 228–42. doi:10.1080/14653240600735875. PMID 16793732.  
  • Hough S, Clements I, Welch P, Wiederholt K (2006). "Differentiation of mouse embryonic stem cells after RNA interference-mediated silencing of OCT4 and Nanog". Stem Cells 24 (6): 1467–75. doi:10.1634/stemcells.2005-0475. PMID 16456133.  
  • Feldman N, Gerson A, Fang J et al. (2006). "G9a-mediated irreversible epigenetic inactivation of Oct-3/4 during early embryogenesis". Nat. Cell Biol. 8 (2): 188–94. doi:10.1038/ncb1353. PMID 16415856.  
  • Boyer L, Lee T, Cole M et al. (2005). "Core transcriptional regulatory circuitry in human embryonic stem cells". Cell 122 (6): 947–56. doi:10.1016/j.cell.2005.08.020. PMID 16153702.  
  • Gerrard L, Zhao D, Clark A, Cui W (2005). "Stably transfected human embryonic stem cell clones express OCT4-specific green fluorescent protein and maintain self-renewal and pluripotency". Stem Cells 23 (1): 124–33. doi:10.1634/stemcells.2004-0102. PMID 15625129.  
  • Reményi A, Lins K, Nissen L et al. (2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes Dev. 17 (16): 2048–59. doi:10.1101/gad.269303. PMID 12923055.  
  • Takeda J, Seino S, Bell GI (1992). "Human Oct3 gene family: cDNA sequences, alternative splicing, gene organization, chromosomal location, and expression at low levels in adult tissues". Nucleic Acids Res. 20 (17): 4613–20. doi:10.1093/nar/20.17.4613. PMID 1408763.  
  • Schoorlemmer J, Kruijer W (1992). "Octamer-dependent regulation of the kFGF gene in embryonal carcinoma and embryonic stem cells". Mech. Dev. 36 (1-2): 75–86. doi:10.1016/0925-4773(91)90074-G. PMID 1723621.  
  • Wey E, Lyons GE, Schäfer BW (1994). "A human POU domain gene, mPOU, is expressed in developing brain and specific adult tissues". Eur. J. Biochem. 220 (3): 753–62. doi:10.1111/j.1432-1033.1994.tb18676.x. PMID 7908264.  
  • Crouau-Roy B, Amadou C, Bouissou C, et al. (1994). "Localization of the OTF3 gene within the human MHC class I region by physical and meiotic mapping". Genomics 21 (1): 241–3. doi:10.1006/geno.1994.1249. PMID 8088794.  
  • Guillaudeux T, Mattei MG, Depetris D, et al. (1993). "In situ hybridization localizes the human OTF3 to chromosome 6p21.3→p22 and OTF3L to 12p13". Cytogenet. Cell Genet. 63 (4): 212–4. doi:10.1159/000133537. PMID 8500351.  
  • Abdel-Rahman B, Fiddler M, Rappolee D, Pergament E (1996). "Expression of transcription regulating genes in human preimplantation embryos". Hum. Reprod. 10 (10): 2787–92. PMID 8567814.  
  • Hillier LD, Lennon G, Becker M, et al. (1997). "Generation and analysis of 280,000 human expressed sequence tags". Genome Res. 6 (9): 807–28. doi:10.1101/gr.6.9.807. PMID 8889549.  
  • Inamoto S, Segil N, Pan ZQ, et al. (1997). "The cyclin-dependent kinase-activating kinase (CAK) assembly factor, MAT1, targets and enhances CAK activity on the POU domains of octamer transcription factors". J. Biol. Chem. 272 (47): 29852–8. doi:10.1074/jbc.272.47.29852. PMID 9368058.  
  • Nichols J, Zevnik B, Anastassiadis K, et al. (1998). "Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4". Cell 95 (3): 379–91. doi:10.1016/S0092-8674(00)81769-9. PMID 9814708.  
  • Gonzalez MI, Robins DM (2001). "Oct-1 preferentially interacts with androgen receptor in a DNA-dependent manner that facilitates recruitment of SRC-1". J. Biol. Chem. 276 (9): 6420–8. doi:10.1074/jbc.. PMID 11096094.  
  • Butteroni C, De Felici M, Schöler HR, Pesce M (2001). "Phage display screening reveals an association between germline-specific transcription factor Oct-4 and multiple cellular proteins". J. Mol. Biol. 304 (4): 529–40. doi:10.1006/jmbi.2000.4238. PMID 11099378.  
  • Ezashi T, Ghosh D, Roberts RM (2001). "Repression of Ets-2-induced transactivation of the tau interferon promoter by Oct-4". Mol. Cell. Biol. 21 (23): 7883–91. doi:10.1128/MCB.21.23.7883-7891.2001. PMID 11689681.  
  • Guo Y, Costa R, Ramsey H, et al. (2002). "The embryonic stem cell transcription factors Oct-4 and FoxD3 interact to regulate endodermal-specific promoter expression". Proc. Natl. Acad. Sci. U.S.A. 99 (6): 3663–7. doi:10.1073/pnas.062041099. PMID 11891324.  
  • Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMID 12477932.  
  • Looijenga LH, Stoop H, de Leeuw HP, et al. (2003). "POU5F1 (OCT3/4) identifies cells with pluripotent potential in human germ cell tumors". Cancer Res. 63 (9): 2244–50. PMID 12727846.  
  • Wang P, Branch DR, Bali M, et al. (2003). "The POU homeodomain protein OCT3 as a potential transcriptional activator for fibroblast growth factor-4 (FGF-4) in human breast cancer cells". Biochem. J. 375 (Pt 1): 199–205. doi:10.1042/BJ20030579. PMID 12841847.  
  • Reményi A, Lins K, Nissen LJ, et al. (2003). "Crystal structure of a POU/HMG/DNA ternary complex suggests differential assembly of Oct4 and Sox2 on two enhancers". Genes Dev. 17 (16): 2048–59. doi:10.1101/gad.269303. PMID 12923055.  
  • Rajpert-De Meyts E, Hanstein R, Jørgensen N, et al. (2004). "Developmental expression of POU5F1 (OCT-3/4) in normal and dysgenetic human gonads". Hum. Reprod. 19 (6): 1338–44. doi:10.1093/humrep/deh265. PMID 15105401.  
  • Matin MM, Walsh JR, Gokhale PJ, et al. (2005). "Specific knockdown of Oct4 and beta2-microglobulin expression by RNA interference in human embryonic stem cells and embryonic carcinoma cells". Stem Cells 22 (5): 659–68. doi:10.1634/stemcells.22-5-659. PMID 15342930.  
  • Baal N, Reisinger K, Jahr H, et al. (2005). "Expression of transcription factor Oct-4 and other embryonic genes in CD133 positive cells from human umbilical cord blood". Thrombosis and Haemostasis 92 (4): 767–75. doi:10.1160/TH04-02-0079. PMID 15467907.  

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