Erk1/2 MAP kinases are required for epidermal G2/M progression.
Erk1/2 mitogen-activated protein kinases (MAPKs) are often hyperactivated in human cancers, where they affect multiple processes, including proliferation. However, the effects of Erk1/2 loss in normal epithelial tissue, the setting of most extracellular signal-regulated kinase (Erk)-associated neoplasms, are unknown. In epidermis, loss of Erk1 or Erk2 individually has no effect, whereas simultaneous Erk1/2 depletion inhibits cell division, demonstrating that these MAPKs are necessary for normal tissue self-renewal. Growth inhibition caused by Erk1/2 loss is rescued by reintroducing Erk2, but not by activating Erk effectors that promote G1 cell cycle progression. Unlike fibroblasts, in which Erk1/2 loss decreases cyclin D1 expression and induces G1/S arrest, Erk1/2 loss in epithelial cells reduces cyclin B1 and c-Fos expression and induces G2/M arrest while disrupting a gene regulatory network centered on cyclin B1-Cdc2. Thus, the cell cycle stages at which Erk1/2 activity is required vary by cell type, with Erk1/2 functioning in epithelial cells to enable progression through G2/M.
Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
Phillip A
PA
Dumesic
Florence A
FA
Scholl
Deborah I
DI
Barragan
Paul A
PA
Khavari
D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics; D002453:Cell Cycle / Q000502:physiology*; D002455:Cell Division / Q000502:physiology*; D019926:Cyclin B / Q000235:genetics; D056744:Cyclin B1; D004789:Enzyme Activation; D000078404:Epidermal Cells; D004817:Epidermis / Q000502:physiology; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology / Q000502:physiology; D016195:G2 Phase / Q000502:physiology*; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology / Q000637:transplantation; D051379:Mice; D016513:Mice, SCID; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009369:Neoplasms / Q000201:enzymology / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D014183:Transplantation, Heterologous
C534699:CCNB1 protein, human; C534700:Ccnb1 protein, mouse; D019926:Cyclin B; D056744:Cyclin B1; D034741:RNA, Small Interfering; D016203:CDC2 Protein Kinase; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3