title: The N-Terminal Phosphorylation of RB by p38 Bypasses Its Inactivation by CDKs and Prevents Proliferation in Cancer Cells.
abstract: Control of the G1/S phase transition by the Retinoblastoma (RB) tumor suppressor is critical for the proliferation of normal cells in tissues, and its inactivation is one of the most fundamental events leading to cancer. Cyclin-dependent kinase (CDK) phosphorylation inactivates RB to promote cell cycle-regulated gene expression. Here we show that, upon stress, the p38 stress-activated protein kinase (SAPK) maximizes cell survival by downregulating E2F gene expression through the targeting of RB. RB undergoes selective phosphorylation by p38 in its N terminus; these phosphorylations render RB insensitive to the inactivation by CDKs. p38 phosphorylation of RB increases its affinity toward the E2F transcription factor, represses gene expression, and delays cell-cycle progression. Remarkably, introduction of a RB phosphomimetic mutant in cancer cells reduces colony formation and decreases their proliferative and tumorigenic potential in mice.
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Albert
authors.initials: A
authors.lastname: Gubern
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Joaquin
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Departament de Ciències Experimentals i de la Salut, UPF, 08003 Barcelona, Spain.
authors.forename: Miriam
authors.initials: M
authors.lastname: Marquès
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Maseres
authors.affiliation: Structural Bioinformatics Group (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Garcia
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Amat
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: González-Nuñez
authors.affiliation: Structural Bioinformatics Group (GRIB), Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain.
authors.forename: Baldo
authors.initials: B
authors.lastname: Oliva
authors.affiliation: Epithelial Carcinogenesis Group, Cancer Cell Biology Programme, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Departament de Ciències Experimentals i de la Salut, UPF, 08003 Barcelona, Spain.
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain. Electronic address: eulalia.nadal@upf.edu.
authors.forename: Eulàlia
authors.initials: E
authors.lastname: de Nadal
authors.affiliation: Cell Signaling Research Group, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain. Electronic address: francesc.posas@upf.edu.
authors.forename: Francesc
authors.initials: F
authors.lastname: Posas
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018844:Cyclin-Dependent Kinases / Q000235:genetics* / Q000378:metabolism; D050684:E2F Transcription Factors / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018716:Molecular Mimicry; D010766:Phosphorylation; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016160:Retinoblastoma Protein / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D050684:E2F Transcription Factors; D011993:Recombinant Fusion Proteins; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4