title: Deregulation of the pRb-E2F4 axis alters epidermal homeostasis and favors tumor development.
abstract: E2F/RB activity is altered in most human tumors. The retinoblastoma family of proteins plays a key role in regulating the progression of the cell cycle from the G1 to S phases. This is achieved through negative regulation of E2F transcription factors, important positive regulators of cell cycle entry. E2F family members are divided into two groups: activators (E2F1-E2F3a) and repressors (E2F3b-E2F8). E2F4 accounts for a large part of the E2F activity and is a main E2F repressor member in vivo. Perturbations in the balance from quiescence towards proliferation contribute to increased mitotic gene expression levels frequently observed in cancer. We have previously reported that combined Rb1-Rbl1 or Rb1-E2f1 ablation in epidermis produces important alterations in epidermal proliferation and differentiation, leading to tumor development. However, the possible roles of E2F4 in this context are still to be determined. Here, we show the absence of any discernible phenotype in the skin of mice lacking of E2f4. In contrast, the inducible loss of Rb1 in the epidermis of E2F4-null mice produced multiple skin abnormalities including altered differentiation and proliferation, spontaneous wounds, carcinoma in situ development and stem cell perturbations. All these phenotypic alterations are associated with extensive gene expression changes, the induction of c-myc and the Akt activation. Moreover the whole transcriptome analyses in comparison with previous models generated also revealed extensive changes in multiple repressive complexes and in transcription factor activity. These results point to E2F4 as a master regulator in multiple steps of epidermal homeostasis in Rb1 absence.
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.|Present address: Unidad Mixta Roche-Chus, Hospital Universitario, 15706 Santiago de Compostela, Spain.
authors.forename: Clotilde
authors.initials: C
authors.lastname: Costa
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.|Unidad de Oncología Molecular y Celular, Instituto de Investigaciones Biomed, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Mirentxu
authors.initials: M
authors.lastname: Santos
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.|Unidad de Oncología Molecular y Celular, Instituto de Investigaciones Biomed, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Mónica
authors.initials: M
authors.lastname: Martínez-Fernández
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.|Unidad de Oncología Molecular y Celular, Instituto de Investigaciones Biomed, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Corina
authors.initials: C
authors.lastname: Lorz
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Lázaro
authors.affiliation: Unidad de Oncología Molecular, CIEMAT (ed70A), 28040 Madrid, Spain.|Unidad de Oncología Molecular y Celular, Instituto de Investigaciones Biomed, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.
authors.forename: Jesús M
authors.initials: JM
authors.lastname: Paramio
keywords: E2F4; Rb; cancer; epidermis; mouse