Activation of p38- and CRM1-dependent nuclear export promotes E2F1 degradation during keratinocyte differentiation

• Published in: Oncogene Vol. 26; no. 8; pp. 1147 - 1154
• Main Authors: IVANOVA, I. A, DAGNINO, L
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 22-02-2007; Nature Publishing Group
• Subjects: Active Transport, Cell Nucleus; Animals; Apoptosis; Biological and medical sciences; Cell differentiation; Cell Differentiation - genetics; Cell Nucleus - chemistry; Cell Nucleus - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells, Cultured; Cellular biology; Cyclin A; Cytoplasm - chemistry; Cytoplasm - metabolism; Degradation; DNA repair; Down-Regulation; E2F1 protein; E2F1 Transcription Factor - analysis; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Enzyme Activation; Exportin 1 Protein; Fundamental and applied biological sciences. Psychology; Genetic aspects; Health aspects; Karyopherins - metabolism; Keratinocytes; Keratinocytes - chemistry; Keratinocytes - cytology; Keratinocytes - metabolism; Kinases; MAP kinase; Mice; Molecular and cellular biology; Mutation; N-Terminus; Nuclear transport; p38 Mitogen-Activated Protein Kinases - metabolism; Physiological aspects; Post-transcription; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Protein kinase C; Protein Structure, Tertiary; Proteins; Receptors, Cytoplasmic and Nuclear - metabolism; Signal Transduction; Tumor suppressor genes; Ubiquitin - metabolism; Ubiquitination; Canada; E2F; Keratinocyte; Activation; Nucleocytoplasmic transport; Differentiation; Carcinogenesis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1209894

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.