FOXO transcription factors in ageing and cancer.

Ageing is associated with an increased onset of cancer. Understanding the molecular mechanisms that underlie the age dependency of cancer will have important implications for preventing and treating this pathology. The signalling pathway connecting insulin and FOXO transcription factors provides the most compelling example for a conserved genetic pathway at the interface between ageing and cancer. FOXO transcription factors (FOXO) promote longevity and tumour suppression. FOXO transcription factors are directly phosphorylated in response to insulin/growth factor signalling by the protein kinase Akt, thereby causing their sequestration in the cytoplasm. In the absence of insulin/growth factors, FOXO factors translocate to the nucleus where they trigger a range of cellular responses, including resistance to oxidative stress, a phenotype highly coupled with lifespan extension. FOXO factors integrate stress stimuli via phosphorylation, acetylation and mono-ubiquitination of a series of regulatory sites. Understanding how FOXO proteins integrate environmental conditions to control specific gene expression programmes will be pivotal in identifying ways to slow the onset of cancer in ageing individuals.

Granzyme A activates an endoplasmic reticulum-associated caspase-independent nuclease to induce single-stranded DNA nicks.

The cytotoxic T lymphocyte protease granzyme A (GzmA) initiates a novel caspase-independent cell death pathway characterized by single-stranded DNA nicking. The previously identified GzmA substrate SET is in a multimeric 270-420-kDa endoplasmic reticulum-associated complex that also contains the tumor suppressor protein pp32. GzmA cleaved the nucleosome assembly protein SET after Lys(176) and disrupted its nucleosome assembly activity. The purified SET complex required only GzmA to reconstitute single-stranded DNA nicking in isolated nuclei. DNA nicking occurred independently of caspase activation. The SET complex contains a 25-kDa Mg(2+)-dependent nuclease that degrades calf thymus DNA and plasmid DNA. Thus, GzmA activates a DNase (GzmA-activated DNase) within the SET complex to produce a novel form of DNA damage during cytotoxic T lymphocyte-mediated death.