Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation.
E2F factors modulate a plethora of cell functions, including proliferation, differentiation, DNA repair and apoptosis. We have shown that differentiation in primary epidermal keratinocytes leads to E2F1 downregulation via activation of protein kinase C and p38 mitogen-activated protein kinase. We now demonstrate that E2F1 downregulation in differentiating keratinocytes involves its ubiquitination, as well as proteasomal degradation subsequent to CRM1-dependent nuclear export. E2F1 nuclear export specifically in response to differentiation requires regions adjacent to the cyclin A-binding domain in the N-terminus of this protein. Significantly, inhibition of p38 interferes with nuclear export and degradation of E2F1 during differentiation, but has no effect on E2F1 in undifferentiated cells. Thus, induction of differentiation in epidermal keratinocytes activates a specific program for post-transcriptional downregulation of E2F1, which involves signaling through p38 and activation of nuclear export pathways.
Ivanova
I A
IA
Department of Physiology and Pharmacology and Regulatory Biology, University of Western Ontario, London, Ontario, Canada.
Dagnino
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L
D021581:Active Transport, Cell Nucleus; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D002467:Cell Nucleus / Q000737:chemistry / Q000378:metabolism*; D002478:Cells, Cultured; D003593:Cytoplasm / Q000737:chemistry / Q000378:metabolism; D015536:Down-Regulation; D050687:E2F1 Transcription Factor / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D028884:Karyopherins / Q000378:metabolism*; D015603:Keratinocytes / Q000737:chemistry / Q000166:cytology* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000097606:Exportin 1 Protein
D050687:E2F1 Transcription Factor; D028884:Karyopherins; D046988:Proteasome Endopeptidase Complex; D018160:Receptors, Cytoplasmic and Nuclear; D025801:Ubiquitin; D048051:p38 Mitogen-Activated Protein Kinases; D000097606:Exportin 1 Protein