CARF Binds to Three Members (ARF, p53, and HDM2) of the p53 Tumor-Suppressor Pathway

摘要

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.