| The C-terminal pentapeptide of Nanog tryptophan repeat domain interacts with Nac1 and regulates stem cell proliferation but not pluripotency. | |
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MedLine Citation:
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PMID: 19366700 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Overexpression of Nanog in mouse embryonic stem (ES) cells has been shown to abrogate the requirement of leukemia inhibitory factor for self-renewal in culture. Little is known about the molecular mechanism of Nanog function. Here we describe the role of the tryptophan repeat (WR) domain, one of the two transactivators at its C terminus, in regulating stem cell proliferation as well as pluripotency. We first created a supertransactivator, W2W3x10, by duplicating repeats W2W3 10 times and discovered that it can functionally substitute for wild type WR at sustaining pluripotency, albeit with a significantly slower cell cycle, phenocopying Nanog(9W) with the C-terminal pentapeptide (WNAAP) of WR deleted. ES cells carrying both W2W3x10 and Nanog(9W) have a longer G1 phase, a shorter S phase in cell cycle distribution and progression analysis, and a lower level of pAkt(Ser473) compared with wild type Nanog, suggesting that both mutants impact the cell cycle machinery via the phosphatidylinositol 3-kinase/Akt pathway. Both mutants remain competent in dimerizing with Nanog but cannot form a complex with Nac1 efficiently, suggesting that WNAAP may be involved in Nac1 binding. By tagging Gal4DBD with WNAAP, we demonstrated that this pentapeptide is sufficient to confer Nac1 binding. Furthermore, we can rescue W2W3x10 by placing WNAAP at the corresponding locations. Finally, we found that Nanog and Nac1 synergistically up-regulate ERas expression and promote the proliferation of ES cells. These results suggest that Nanog interacts with Nac1 through WNAAP to regulate the cell cycle of ES cells via the ERas/phosphatidylinositol 3-kinase/Akt pathway, but not pluripotency, thus decoupling cell cycle control from pluripotency. |
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Authors:
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Tianhua Ma; Zhe Wang; Yunqian Guo; Duanqing Pei |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-04-14 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 284 ISSN: 0021-9258 ISO Abbreviation: J. Biol. Chem. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-06-08 Completed Date: 2009-08-20 Revised Date: 2011-11-03 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 16071-81 Citation Subset: IM |
Affiliation:
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Laboratory of Stem Cell Biology, Department of Biological Sciences and Biotechnology, Institutes of Biomedicine, School of Medicine, Tsinghua University, Beijing 100084, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Cell Differentiation / physiology Cell Division / physiology Cells, Cultured Embryonic Stem Cells / cytology*, physiology* Gene Expression Regulation, Developmental Homeodomain Proteins* / chemistry, genetics, metabolism Humans Kidney / cytology Mice Molecular Sequence Data Mutagenesis Nerve Tissue Proteins / metabolism* Oncogene Protein p21(ras) / metabolism Phosphatidylinositol 3-Kinases / metabolism Pluripotent Stem Cells / cytology, physiology Protein Structure, Tertiary Proto-Oncogene Proteins c-akt / metabolism Reverse Transcriptase Polymerase Chain Reaction S Phase / physiology Structure-Activity Relationship Transcriptional Activation / physiology Tryptophan / chemistry, metabolism |
| Chemical | |
Reg. No./Substance:
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0/ERas protein, mouse; 0/Homeodomain Proteins; 0/Nacc1 protein, mouse; 0/Nanog protein, mouse; 0/Nerve Tissue Proteins; 73-22-3/Tryptophan; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; EC 3.6.5.2/Oncogene Protein p21(ras) |
| Comments/Corrections | |
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