Differential Role for Transcription Factor Oct4 Nucleocytoplasmic Dynamics in Somatic Cell Reprogramming and Self-renewal of Embryonic Stem Cells

Oka, Masahiro; Moriyama, Tetsuji; Asally, Munehiro; Kawakami, Koichi; Yoneda, Yoshihiro

doi:10.1074/jbc.m112.448837

Cited by 38 publications

(38 citation statements)

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“…In iPSCs, studies have shown that OCT4 is localised to the nucleus in undifferentiated iPSCs generated through lentivirus-mediated transduction of OCT4, SOX2, NANOG and LIN28 in foreskin cells 10. However, OCT4 mutants containing a nuclear export signal (NES), which were primarily localised to the cytoplasm, have also been shown to maintain the undifferentiated state of human embryonic stem cells (hESCs),11 suggesting that the localisation of OCT4 is insignificant as long as nuclear processing is maintained. Immunohistochemical (IHC) staining was used to identify cytoplasmic OCT4 in CSC subpopulations in two groups of oral cavity squamous cell carcinomas (SCC) (figure 2A),12 13 with a third group showing both nuclear and cytoplasmic localisation,14 consistent with findings in other tumours such as glioma15 and the epithelial cells of CRC 5.…”

Section: Octamer-binding Transcription Factormentioning

confidence: 99%

Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

et al. 2017

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The stem cell markers octamer-binding transcription factor 4, sex-determining region Y-box 2, NANOG, Kruppel-like factor 4 and c-MYC are key factors in inducing pluripotency in somatic cells, and they have been used to detect cancer stem cell subpopulations in a range of cancer types. Recent literature has described the subcellular localisation of these markers and their potential implications on cellular function. This is a relatively complex and unexplored area of research, and the extent of the effect that subcellular localisation has on cancer development and growth is largely unknown. This review analyses this area of research in the context of the biology of stem cells and cancer and explores the potential modulating effect of subcellular localisation of these proteins as supported by the literature.

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Section: Octamer-binding Transcription Factormentioning

confidence: 99%

Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

et al. 2017

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“…For this process, not only does OCT4 control transcriptional machinery, but OCT4 also acts as a nucleocytoplasmic shuttling protein. For example, OCT4-mutant ESCs with altered nuclear import/export activity display limited potential for cellular reprogramming, suggesting a nucleocytoplasmic shuttling role of OCT4 in somatic cell reprogramming [67]. In mature human oocytes, OCT4 is expressed in the cytoplasm throughout the cleavage stage before compaction, after which OCT4 can be detected in the nucleus throughout the blastocyst and in PGCs at the time of their development in the early fetus [68].…”

Section: Fig 3 (A)mentioning

confidence: 99%

Direct Reprogramming of Human Primordial Germ Cells into Induced Pluripotent Stem Cells: Efficient Generation of Genetically Engineered Germ Cells

Bazley

Liu

Yuan

et al. 2015

Stem Cells and Development

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Primordial germ cells (PGCs) share many properties with embryonic stem cells (ESCs) and innately express several key pluripotency-controlling factors, including OCT4, NANOG, and LIN28. Therefore, PGCs may provide a simple and efficient model for studying somatic cell reprogramming to induced pluripotent stem cells (iPSCs), especially in determining the regulatory mechanisms that fundamentally define pluripotency. Here, we report a novel model of PGC reprogramming to generate iPSCs via transfection with SOX2 and OCT4 using integrative lentiviral. We also show the feasibility of using nonintegrative approaches for generating iPSC from PGCs using only these two factors. We show that human PGCs express endogenous levels of KLF4 and C-MYC protein at levels similar to embryonic germ cells (EGCs) but lower levels of SOX2 and OCT4. Transfection with both SOX2 and OCT4 together was required to induce PGCs to a pluripotent state at an efficiency of 1.71%, and the further addition of C-MYC increased the efficiency to 2.33%. Immunohistochemical analyses of the SOderived PGC-iPSCs revealed that these cells were more similar to ESCs than EGCs regarding both colony morphology and molecular characterization. Although leukemia inhibitory factor (LIF) was not required for the generation of PGC-iPSCs like EGCs, the presence of LIF combined with ectopic exposure to C-MYC yielded higher efficiencies. Additionally, the SO-derived PGC-iPSCs exhibited differentiation into representative cell types from all three germ layers in vitro and successfully formed teratomas in vivo. Several lines were generated that were karyotypically stable for up to 24 subcultures. Their derivation efficiency and survival in culture significantly supersedes that of EGCs, demonstrating their utility as a powerful model for studying factors regulating pluripotency in future studies.

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Section: Discussionunclassified

“…Un resultado similar se observa con la presencia nuclear de OCT-4 en células periciticas en cultivo, y que es diferente para la distribución citoplasmática de OCT-4 de las células en aorta. Esta explicación parece consistente con la diferente expresión génica de OCT-4 de la isoforma B y de la isoforma A, además por el comportamiento dinámico de OCT-4 aún es desconocido (Oka et al, 2013).Oka et al demostraron que OCT-4 es un factor de transcripción que se mantiene translocándose entre el nú-cleo y el citoplasma, además, la mutación de la región de localización nuclear (NLS) del transportador de OCT-4 produce su difusión pasiva desde el núcleo al citoplasma. Siendo los niveles de OCT-4 en el núcleo fundamentales para mantener un estado indiferenciado de la célula, donde la movilización de este factor dentro y fuera del núcleo es clave más que la expresión de este factor de transcripción.…”

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La Translocación in vitro Citoplasma/Núcleo del Factor de Transcripción Embrionario OCT-4 en Células Perivasculares Propone a la Aorta Como un Nicho Quiescente de Células Madres Adultas

Herrera‐Bravo¹,

Montiel-Eulefi²,

Glaser³

et al. 2013

Int. J. Morphol.

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HERRERA-BRAVO, J.; MONTIEL-EULEFI, E.; GLASER, T.; GARCÉS, M; LEAL, P. & HENNING, U. A. La Translocación InVitro Citoplasma/Núcleo del Factor de Transcripción Embrionario OCT-4 en Células Perivasculares Propone a la Arteria Aorta Como un Nicho Quiescente de Células Madre Adultas. Int. J. Morphol., 31(4):1430-1438, 2013. RESUMEN:Las células perivasculares tienen un origen común en las células madre embrionarias y en los vasos sanguíneos que proporcionan un nicho para la mantención de su troncalidad. La expresión de marcadores embrionarios y de células indiferenciadas, como también la gran variedad de fenotipos celulares generados desde los pericitos, podrían ser explicados por la capacidad de estas células de ser inducidas a un estado "stemness" cuando son tratadas con factores adecuados. Nuestros resultados describen la expresión de células con OCT-4 citoplasmático en una ubicación anatómica perivascular donde de su nicho se encuentra en la región intima de la aorta en rata. In vitro las células aisladas por el método de explante que promueve el aislamiento de células migratorias desde los tejidos muestran un fenotipo con un citoplasma alargado y que expresan aSMA, PDGFRa y b, siendo estos dos últimos marcadores específicos de pericitos. En estas células se presenta una tranlocación a la variante nuclear de OCT-4 que ha sido descrito como el principal regulador de los procesos de autorrenovación y pluripotencia. La expresión de OCT-4 confirma y amplía aún más las observaciones obtenidas en nuestras investigaciones anteriores y demuestra que células madre se encuentran en los vasos sanguíneos en un microambiente que, probablemente, les permite que sobrevivan y permanezcan en reposo como un tipo de célula troncal quiescente.PALABRAS CLAVE: Troncalidad; Pericitos; Translocación; OCT-4; Aorta de rata. INTRODUCCIÓNNuestro grupo de investigación, ha identificado que las células perivasculares tienen un origen común en las cé-lulas madre embrionarias y los vasos sanguíneos proporcionan un nicho para la mantención de su troncalidad (MontielEulefi et al., 2009). De esta manera, las células aisladas de los vasos poseen actividad pluripotente y con capacidad de diferenciarse en los distintos tipos celulares provenientes de las tres capas germinativas. Estas células perivasculares presentan un fenotipo de pericitos expresando los marcadores especificos "Thymocyte differentiation antigen 1" (Thy-1/CD90), "alpha-smooth muscle actin" (aSMA), "Plateletderived growth factor receptor a" (PDGFRa) (Montiel-Eulefi et al., 2012;Tárnok et al., 2010).En la actualidad, la idea que todas las células madre mesenquimales son pericitos es un tema en discusión debido a que pueden expresar también marcadores encontrados en este tipo celular (Caplan, 2008;da Silva Meirelles et al., 2008;Dore-Duffy & Cleary, 2011). Los pericitos pueden ser inducidos a un estado embrionario caracterizado por la expresión de "Stage-specific mouse embryonic antigen" (SSEA-1), un antígeno específico presente en células madre embrionarias y a progenitores neuronales...

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Differential Role for Transcription Factor Oct4 Nucleocytoplasmic Dynamics in Somatic Cell Reprogramming and Self-renewal of Embryonic Stem Cells

Cited by 38 publications

References 50 publications

Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

Subcellular localisation of the stem cell markers OCT4, SOX2, NANOG, KLF4 and c-MYC in cancer: a review

Direct Reprogramming of Human Primordial Germ Cells into Induced Pluripotent Stem Cells: Efficient Generation of Genetically Engineered Germ Cells

La Translocación in vitro Citoplasma/Núcleo del Factor de Transcripción Embrionario OCT-4 en Células Perivasculares Propone a la Aorta Como un Nicho Quiescente de Células Madres Adultas

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