title: Differential proteomics analysis reveals a role for E2F2 in the regulation of the Ahr pathway in T lymphocytes.
abstract: E2F transcription factors (E2F1-8) are best known for their role in cell proliferation, although it is clear that they regulate many other biological processes through the transcriptional modulation of distinct target genes. However, the specific set of genes regulated by each E2F remains to be characterized. To gain insight into the molecular pathways regulated by E2F2, we have analyzed the proteome of antigen receptor-activated T cells lacking E2F2. We report that loss of E2F2 results in a deregulated Aryl-hydrocarbon-receptor pathway. Proliferating E2F2(-/-) T lymphocytes expressed significantly higher levels of Aip, Ahr, and Arnt relative to wild-type (WT)(1) controls. The mechanism for increased levels of Aip appears straightforward, involving direct regulation of the Aip gene promoter by E2F2. Although the Ahr and Arnt promoters also bind E2F2, their regulation appears to be more complex. Nevertheless, exposure to the environmental xenobiotic 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a well-known exogenous ligand of the Ahr pathway, led to overexpression of the Ahr target gene Cyp1a1, and to increased sensitivity to TCDD-triggered apoptosis in E2F2(-/-) T cells compared with WT controls. These results suggest that E2F2 modulates cellular sensitivity to xenobiotic signals through the negative regulation of the Ahr pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of the Basque Country, UPV/EHU, 48940 Leioa, Spain.
authors.forename: Mikel
authors.initials: M
authors.lastname: Azkargorta
authors.forename: Asier
authors.initials: A
authors.lastname: Fullaondo
authors.forename: Usua
authors.initials: U
authors.lastname: Laresgoiti
authors.forename: Kerman
authors.initials: K
authors.lastname: Aloria
authors.forename: Arantza
authors.initials: A
authors.lastname: Infante
authors.forename: Jesus M
authors.initials: JM
authors.lastname: Arizmendi
authors.forename: Ana M
authors.initials: AM
authors.lastname: Zubiaga
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D050703:E2F2 Transcription Factor / Q000502:physiology*; D015180:Electrophoresis, Gel, Two-Dimensional; D005434:Flow Cytometry; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010085:Oxidative Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology; D040901:Proteomics; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D050703:E2F2 Transcription Factor; C484940:E2f2 protein, mouse; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon