By Stuart P. Atkinson
Cellular senescence is a mechanism by which dysfunctional or aging cells are growth arrested and plays an important role in controlling tumourigenesis. Senescent cells also accumulate in various tissues and organs with ageing (Campisi, 2005) but whether this is causally implicated in age-related tissue dysfunction and whether their removal is potentially beneficial remains unknown. To better understand this concept, researchers from the laboratory of Jan M. van Deursen at the Mayo Clinic College of Medicine, Minnesota, USA designed a transgenic strategy based on previous work (Pajvani et al), through which senescent cells can be selectively killed by apoptosis upon the administration of AP20187. AP20187 a synthetic drug that induces dimerisation of a membrane-bound myristoylated FK506-binding-protein–Caspase 8 (FKBP–Casp8) fusion protein expressed specifically via a 2,617-bp fragment of the p16Ink4a gene promoter that is transcriptionally active in senescent, but not non-senescent cells (Baker et al). Most senescent cells express p16Ink4a, a cyclin-dependent kinase inhibitor and tumour suppressor that enforces growth arrest by activating the Retinoblastoma (Rb) protein (Rodier and Campisi) and additionally, p16Ink4a expression of is known to increase with ageing in several rodent and human tissues (Krishnamurthy et al). The construct also contained an internal ribosome entry site (IRES) followed by an open reading frame (ORF) coding for enhanced green fluorescence protein (EGFP) to allow for detection of p16Ink4a-positive senescent cells. The construct was injected into fertilized eggs yielding transgenic mouse founder lines, designated INK-ATTAC (INK-linked apoptosis through targeted activation of Caspase).