title: Regulation of DNA synthesis in mouse embryonic stem cells by transforming growth factor-alpha: involvement of the PI3-K/Akt and Notch/Wnt signaling pathways.
abstract: This study examined the mechanisms by which transforming growth factor (TGF)-alpha regulates proliferation of mouse embryonic stem (ES) cells. TGF-alpha increased [3H] thymidine and BrdU incorporation in a time- (0-72 h) and dose-dependent (0-10 ng/ml) manner. TGF-alpha stimulated the phosphorylation of Akt, mammalian target of rapamycin (mTOR), p70S6K1 and p44/42 mitogen-activated protein kinases (MAPKs). TGF-alpha also increased the protein levels of Notch, Notch intracellular domain, Hes-1 and Wnt1. However, TGF-alpha-induced DNA synthesis was blocked by inhibition of Akt, mTOR, p44/42 MAPKs and Notch. TGF-alpha increased the gene expression of c-jun, c-myc and c-fos. Moreover, TGF-alpha increased cyclin D/CDK 4 and cyclin E/CDK 2 levels, while decreasing p21cip1/waf1 and p27kip1, which were blocked by the inhibition of Akt, mTOR and Notch. In conclusion, TGF-alpha regulated DNA synthesis of mouse ES cells via PI3-K/Akt, p44/42 MAPKs and Notch/Wnt pathways.
authors.affiliation: Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea.
authors.forename: Jung Sun
authors.initials: JS
authors.lastname: Heo
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.forename: Ho Jae
authors.initials: HJ
authors.lastname: Han
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects*; D053595:Embryonic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases; D016211:Transforming Growth Factor alpha; D051153:Wnt Proteins; C546842:MTOR protein, human; C546843:mTOR protein, mouse