title: Mutant lamin A links prophase to a p53 independent senescence program.
abstract: Expression of oncogenes or short telomeres can trigger an anticancer response known as cellular senescence activating the p53 and RB tumor suppressor pathways. This mechanism is switched off in most tumor cells by mutations in p53 and RB signaling pathways. Surprisingly, p53 disabled tumor cells could be forced into senescence by expression of a mutant allele of the nuclear envelope protein lamin A. The pro-senescence lamin A mutant contains a deletion in the sequence required for processing by the protease ZMPSTE24 leading to accumulation of farnesylated lamin A in the nuclear envelope. In addition, the serine at position 22, a target for CDK1-dependent phosphorylation, was mutated to alanine, preventing CDK1-catalyzed nuclear envelope disassembly. The accumulation of this mutant lamin A compromised prophase to prometaphase transition leading to invaginations of the nuclear lamina, nuclear fragmentation and impaired chromosome condensation. Cells exited this impaired mitosis without cytokinesis and re-replicated their DNA ultimately arresting in interphase as polyploid cells with features of cellular senescence including increased expression of inflammatory gene products and a significant reduction of tumorigenicity in vivo.
authors.affiliation: a Département de Biochimie ; Université de Montréal ; C.P. 6128; Succ. Center-Ville; Montréal , QC Canada.
authors.forename: Olga
authors.initials: O
authors.lastname: Moiseeva
authors.forename: Frédéric
authors.initials: F
authors.lastname: Lessard
authors.forename: Mariana
authors.initials: M
authors.lastname: Acevedo-Aquino
authors.forename: Mathieu
authors.initials: M
authors.lastname: Vernier
authors.forename: Youla S
authors.initials: YS
authors.lastname: Tsantrizos
authors.forename: Gerardo
authors.initials: G
authors.lastname: Ferbeyre
mesh_terms: D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008565:Membrane Proteins / Q000378:metabolism; D008666:Metalloendopeptidases / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics*; D009685:Nuclear Envelope / Q000378:metabolism; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D034904:Lamin Type A; D008565:Membrane Proteins; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D008666:Metalloendopeptidases; C120130:ZMPSTE24 protein, human
keywords: ZMPSTE24; farnesylation; mitosis; progeria; senescence