Regulation of Ras-MAPK pathway mitogenic activity by restricting nuclear entry of activated MAPK in endoderm differentiation of embryonic carcinoma and stem cells.
In response to retinoic acid, embryonic stem and carcinoma cells undergo differentiation to embryonic primitive endoderm cells, accompanied by a reduction in cell proliferation. Differentiation does not reduce the activation of cellular MAPK/Erk, but does uncouple mitogen-activated protein kinase (MAPK) activation from phosphorylation/activation of Elk-1 and results in inhibition of c-Fos expression, whereas phosphorylation of the cytoplasmic substrate p90RSK remains unaltered. Cell fractionation and confocal immunofluorescence microscopy demonstrated that activated MAPK is restricted to the cytoplasmic compartment after differentiation. An intact actin and microtubule cytoskeleton appears to be required for the restriction of MAPK nuclear entry induced by retinoic acid treatment because the cytoskeletal disrupting agents nocodazole, colchicine, and cytochalasin D are able to revert the suppression of c-Fos expression. Thus, suppression of cell proliferation after retinoic acid-induced endoderm differentiation of embryonic stem and carcinoma cells is achieved by restricting nuclear entry of activated MAPK, and an intact cytoskeleton is required for the restraint.
Ovarian Cancer and Tumor Cell Biology Programs, Dept. of Medical Oncology, Medical Science Division, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111, USA.
Elizabeth R
ER
Smith
Jennifer L
JL
Smedberg
Malgorzata E
ME
Rula
Xiang-Xi
XX
Xu
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018236:Carcinoma, Embryonal; D002454:Cell Differentiation / Q000502:physiology*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism*; D003078:Colchicine / Q000494:pharmacology; D015638:Cytochalasin D / Q000494:pharmacology; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004707:Endoderm / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D015739:Nocodazole / Q000494:pharmacology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013347:Subcellular Fractions / Q000737:chemistry / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D018631:ras Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D005231:Fatty Acids, Unsaturated; D019384:Nucleic Acid Synthesis Inhibitors; D016760:Proto-Oncogene Proteins c-fos; D015638:Cytochalasin D; D014212:Tretinoin; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D015739:Nocodazole; D003078:Colchicine; C038753:leptomycin B