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

• DOI: 10.1196/annals.1395.033
• Publication Date: 2007-04-25T21:14:35Z
• Authors: HASAN M. KAMRUL; RENU WADHWA; SUNIL C. KAUL
• Keywords: Cyclin-Dependent Kinase Inhibitor p21; Proteasome Endopeptidase Complex; 0303 health sciences; Proto-Oncogene Proteins c-mdm2; DNA-Binding Proteins; Mice; 03 medical and health sciences; Gene Expression Regulation; Cell Line, Tumor; Two-Hybrid System Techniques; Tumor Suppressor Protein p14ARF; Animals; Humans; Genes, Tumor Suppressor; Tumor Suppressor Protein p53; DNA Damage; Protein Binding; Transcription Factors

Abstract: The INK4a locus (chromosome 9p21) encodes two structurally distinct tumor‐suppressor proteins, p16INK4a and the alternative reading frame protein, ARF (p19ARF in mouse and p14ARF 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 p19ARF 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‐p21WAF1 pathway that is central to the cell cycle control, senescence, and DNA damage response of human cells.