Phosphorylation of OCT4 Serine 236 Inhibits Germ Cell Tumor Growth by Inducing Differentiation

Octamer-binding transcription factor 4 (Oct4) plays an important role in maintaining pluripotency in embryonic stem cells and is closely related to the malignancies of various cancers. Although posttranslational modifications of Oct4 have been widely studied, most of these have not yet been fully characterized, especially in cancer. In this study, we investigated the role of phosphorylation of serine 236 of OCT4 [OCT4 (S236)] in human germ cell tumors (GCTs). OCT4 was phosphorylated at S236 in a cell cycle-dependent manner in a patient sample and GCT cell lines. The substitution of endogenous OCT4 by a mimic of phosphorylated OCT4 with a serine-to-aspartate mutation at S236 (S236D) resulted in tumor cell differentiation, growth retardation, and inhibition of tumor sphere formation. GCT cells expressing OCT4 S236D instead of endogenous OCT4 were similar to cells with OCT4 depletion at the mRNA transcript level as well as in the phenotype. OCT4 S236D also induced tumor cell differentiation and growth retardation in mouse xenograft experiments. Inhibition of protein phosphatase 1 by chemicals or short hairpin RNAs increased phosphorylation at OCT4 (S236) and resulted in the differentiation of GCTs. These results reveal the role of OCT4 (S236) phosphorylation in GCTs and suggest a new strategy for suppressing OCT4 in cancer.

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Role of Mael in early oogenesis and during germ-cell differentiation from embryonic stem cells in mice in vitro

Zygote ◽

10.1017/s0967199412000743 ◽

2013 ◽

Vol 22 (4) ◽

pp. 513-520 ◽

Cited By ~ 3

Author(s):

I. Bahena ◽

E. Xu ◽

M. Betancourt ◽

E. Casas ◽

Y. Ducolomb ◽

...

Keyword(s):

Stem Cells ◽

Cell Differentiation ◽

Embryonic Stem Cells ◽

Germ Cell ◽

Embryonic Stem ◽

Oocyte Growth ◽

Germ Cell Differentiation ◽

Rnai Technology

SummaryIn a previous study, we have identified a set of conserved spermatogenic genes whose expression is restricted to testis and ovary and that are developmentally regulated. One of these genes, the transcription factor Mael, has been reported to play an essential role in mouse spermatogenesis. Nevertheless, the role of Mael in mouse oogenesis has not been defined. In order to analyse the role of Mael in mouse oogenesis, the expression of this gene was blocked during early oogenesis in mouse in vitro using RNAi technology. In addition, the role of Mael during differentiation of embryonic stem cells (ESC) into germ cells in vitro was analysed. Results show that downregulation of Mael by a specific short interfering RNA disrupted fetal oocyte growth and differentiation in fetal ovary explants in culture and the expression of several germ-cell markers in ESC during their differentiation. These results suggest that there is an important role for Mael in early oogenesis and during germ-cell differentiation from embryonic stem cells in mouse in vitro.

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Anti-tumour activity of interferon-alpha in multiple myeloma: role of interleukin 6 and tumor cell differentiation

British Journal of Haematology ◽

10.1046/j.1365-2141.2003.04255.x ◽

2003 ◽

Vol 121 (2) ◽

pp. 251-258 ◽

Cited By ~ 26

Author(s):

William Matsui ◽

Carol Ann Huff ◽

Milada Vala ◽

James Barber ◽

B. Douglas Smith ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Differentiation ◽

Tumor Cell ◽

Interferon Alpha ◽

Interleukin 6 ◽

Anti Tumour Activity ◽

Tumour Activity ◽

Tumor Cell Differentiation

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Evolving Role of RING1 and YY1 Binding Protein in the Regulation of Germ-Cell-Specific Transcription

Genes ◽

10.3390/genes10110941 ◽

2019 ◽

Vol 10 (11) ◽

pp. 941 ◽

Cited By ~ 4

Author(s):

Izabella Bajusz ◽

Surya Henry ◽

Enikő Sutus ◽

Gergő Kovács ◽

Melinda K. Pirity

Keyword(s):

Retinoic Acid ◽

Cell Differentiation ◽

Germ Cell ◽

Binding Protein ◽

Es Cells ◽

Critical Role ◽

Embryonic Stem ◽

Germ Cell Differentiation ◽

Germline Cells

Separation of germline cells from somatic lineages is one of the earliest decisions of embryogenesis. Genes expressed in germline cells include apoptotic and meiotic factors, which are not transcribed in the soma normally, but a number of testis-specific genes are active in numerous cancer types. During germ cell development, germ-cell-specific genes can be regulated by specific transcription factors, retinoic acid signaling and multimeric protein complexes. Non-canonical polycomb repressive complexes, like ncPRC1.6, play a critical role in the regulation of the activity of germ-cell-specific genes. RING1 and YY1 binding protein (RYBP) is one of the core members of the ncPRC1.6. Surprisingly, the role of Rybp in germ cell differentiation has not been defined yet. This review is focusing on the possible role of Rybp in this process. By analyzing whole-genome transcriptome alterations of the Rybp-/- embryonic stem (ES) cells and correlating this data with experimentally identified binding sites of ncPRC1.6 subunits and retinoic acid receptors in ES cells, we propose a model how germ-cell-specific transcription can be governed by an RYBP centered regulatory network, underlining the possible role of RYBP in germ cell differentiation and tumorigenesis.

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