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.
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.
Heo
Jung Sun
JS
Department of Veterinary Physiology, Biotherapy Human Resources Center (BK 21), College of Veterinary Medicine, Chonnam National University, Gwangju, South Korea.
Lee
Sang Hun
SH
Han
Ho Jae
HJ
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*
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