Abstract
The INK4a locus on 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 role in senescence of primary cells and activates pathways for cell cycle control and tumor suppression. The current prevailing model proposes that p19(ARF) activates p53 function by antagonizing its degradation by MDM2. It was, however, recently shown that stabilization of p53 by p14(ARF) occurs independent of the relocalization of MDM2 to the nucleolus. We have identified a novel collaborator of ARF, CARF. It co-localizes and interacts with ARF in the nucleolus. We demonstrate that CARF is co-regulated with ARF, cooperates with it in activating p53, and thus acts as a novel component of the ARF-p53-p21 pathway.
Highlights
The INK4a locus on chromosome 9p21 is frequently affected in human tumors
To isolate p19ARF-interacting proteins, a Gal4 binding domain (BD)-p19ARF fusion protein was used as a bait to screen a human cDNA library cloned into a Gal4 activation domain (AD) yeast two-hybrid plasmid
The results revealed that p19ARF (Fig. 1A) interacts with CARF
Summary
The INK4a locus on chromosome 9p21 is frequently affected in human tumors. It encodes two structurally distinct tumor suppressor proteins, p16INK4a and the alternative reading frame protein, ARF (p14ARF in human and p19ARF in mouse) [1,2,3,4,5]. Co-localization of CARF and ARF was seen in the granular region of the nucleolus of NARF cells. HeLa cells stained for endogenous CARF and endogenous ARF showed co-localization of the proteins in the granular region of the nucleolus (j–l).
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