title: Loss of p53 induces cell proliferation via Ras-independent activation of the Raf/Mek/Erk signaling pathway.
abstract: The Ras family of small GTPases constitutes a central node in the transmission of mitogenic stimuli to the cell cycle machinery. The ultimate receptor of these mitogenic signals is the retinoblastoma (Rb) family of pocket proteins, whose inactivation is a required step to license cell proliferation. However, little is known regarding the molecular events that connect Ras signaling with the cell cycle. Here, we provide genetic evidence to illustrate that the p53/p21 Cdk-interacting protein 1 (Cip1)/Rb axis is an essential component of the Ras signaling pathway. Indeed, knockdown of p53, p21Cip1, or Rb restores proliferative properties in cells arrested by ablation of the three Ras loci, H-, N- and K-Ras. Ras signaling selectively inactivates p53-mediated induction of p21Cip1 expression by inhibiting acetylation of specific lysine residues in the p53 DNA binding domain. Proliferation of cells lacking both Ras proteins and p53 can be prevented by reexpression of the human p53 ortholog, provided that it retains an active DNA binding domain and an intact lysine residue at position 164. These results unveil a previously unidentified role for p53 in preventing cell proliferation under unfavorable mitogenic conditions. Moreover, we provide evidence that cells lacking Ras and p53 proteins owe their proliferative properties to the unexpected retroactivation of the Raf/Mek/Erk cascade by a Ras-independent mechanism.
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and mdrosten@cnio.es mbarbacid@cnio.es.
authors.forename: Matthias
authors.initials: M
authors.lastname: Drosten
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and.
authors.forename: Eleanor Y M
authors.initials: EY
authors.lastname: Sum
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and.
authors.forename: Carmen G
authors.initials: CG
authors.lastname: Lechuga
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and.
authors.forename: Lucía
authors.initials: L
authors.lastname: Simón-Carrasco
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and.
authors.forename: Harrys K C
authors.initials: HK
authors.lastname: Jacob
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and.
authors.forename: Raquel
authors.initials: R
authors.lastname: García-Medina
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Sidong
authors.initials: S
authors.lastname: Huang
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Division of Molecular Carcinogenesis and Center for Biomedical Genetics, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.
authors.forename: Rene
authors.initials: R
authors.lastname: Bernards
authors.affiliation: Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, 28029 Madrid, Spain; and mdrosten@cnio.es mbarbacid@cnio.es.
authors.forename: Mariano
authors.initials: M
authors.lastname: Barbacid
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D011905:Genes, ras; D006801:Humans; D008239:Lysine / Q000737:chemistry; D020935:MAP Kinase Signaling System; D051379:Mice; D008856:Microscopy, Fluorescence; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D048490:raf Kinases / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D018631:ras Proteins; D008239:Lysine