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.