CARF binds to three members (ARF, p53, and HDM2) of the p53 tumor-suppressor pathway.

The INK4a locus (chromosome 9p21) encodes two structurally distinct tumor-suppressor proteins, p16(INK4a) and the alternative reading frame protein, ARF (p19(ARF) in mouse and p14(ARF) in human). Each of these proteins has a major role in cell cycle control and senescence pathways. We originally identified a novel collaborator of ARF, CARF, from a two-hybrid interactive screen using p19(ARF) as bait and found that CARF interacts with ARF in the perinucleolar region and activates p53 function. In the absence of ARF, it interacts with p53 directly leading to ARF-independent enhancement of p53 function and in turn undergoes a negative feedback regulation. Very recently, we found that CARF interacts with HDM2 and undergoes degradation by an HDM2-dependent proteasome pathway. CARF may exert a vital control on p53-HDM2-p21(WAF1) pathway that is central to the cell cycle control, senescence, and DNA damage response of human cells.