Figure 1.

Senescence after growth arrest. The molecular and genetic insights into the mechanism of cyclin dependent kinase 4 (CDK4) inhibition therapy induced senescence in mammalian cell lines. The progression into senescence follows CDK4 inhibitor dependent growth arrest with the dissociation of the HAUSP (herpesvirus associated ubiquitin specific peptidase 7) deubiquitinase from MDM2 proto-oncogene (MDM2), allowing its turnover.² A yet unidentified MDM2 substrate, here called atropos, is likely allowed to accumulate as MDM2 levels decrease prompting the transition of the cell along a path to senescence. ATRX is a multifaceted regulator of this process playing roles in MDM2 turnover², HRAS (Harvey rat sarcoma viral oncogene homolog) transcription⁷ and senescence associated heterochromatic foci (SAHF) formation and maintenance.⁷ Phenotypes and markers are indicated in the blue circles (SAHF; SA-β-gal, senescence associated beta-galactosidase activity; SASP, senescence associated secretory program; LTC, long term durable stable clonogenic growth arrest upon replating in the absence of drug; PML, promyelocytic leukemia protein foci detection; ATRX, α-thalassemia, mental retardation, X-linked foci detection). Colors indicate different pathways, with broken arrows remaining to be mechanistically elucidated.