Abstract
Suppression of tumorigenesis is considerably more stringent in the human than in the much shorter lived mouse species, and the reasons for this difference are poorly understood. We investigated functional differences in the control of the ARF (alternative reading frame) protein that acts upstream of p53 and is encoded along with p16(INK4a) at a major tumor suppressor locus in both the human and mouse genomes. The mouse and human ARF proteins are substantially divergent at their carboxyl termini. We have shown that the mouse ARF protein (p19ARF) interacts with Pex19p in the cell cytoplasm leading to its nuclear exclusion and repression of its p53 activation function. The human ARF protein (p14ARF) is substantially smaller than its mouse counterpart and is not subject to this functional inactivation by Pex19p. In an identical cellular background, ribozymes directed against Pex19p enhanced p19ARF- but not p14ARF-activated p53 function. This is the first demonstration of a functional difference between the mouse and human ARF proteins. In view of the major role of ARF in tumor suppression, this distinction may contribute to the different levels of tumor proneness of these species.
Highlights
The INK4a (MTS1, CDKN2) locus on chromosome 9p21 encodes two unrelated tumor suppressor proteins: p16INK4a, an inhibitor of the cyclin D-dependent kinase that acts upstream of the retinoblastoma protein, pRb, and p19ARF, an alternative reading frame protein that acts upstream of p53 [1,2,3,4,5,6,7,8]
We have shown that the mouse ARF protein (p19ARF) interacts with Pex19p in the cell cytoplasm leading to its nuclear exclusion and repression of its p53 activation function
Each of these proteins has a role in the senescence of primary cells, activates pathways for cell cycle control and tumor suppression [5, 9, 10, 12,13,14,15], and is often functionally inactivated in human tumors (8, 16 –20). p16INK4a inhibits the activity of cyclindependent kinases and prevents the phosphorylation and functional inactivation of pRB [21, 22]. p19ARF and its human homologue, p14ARF, activate p53 function by restraining the p53 antagonist, MDM2 [23,24,25,26,27]
Summary
The INK4a (MTS1, CDKN2) locus on chromosome 9p21 encodes two unrelated tumor suppressor proteins: p16INK4a, an inhibitor of the cyclin D-dependent kinase that acts upstream of the retinoblastoma protein, pRb, and p19ARF, an alternative reading frame protein that acts upstream of p53 [1,2,3,4,5,6,7,8]. We have shown that the mouse ARF protein (p19ARF) interacts with Pex19p in the cell cytoplasm leading to its nuclear exclusion and repression of its p53 activation function. The human ARF protein (p14ARF) is substantially smaller than its mouse counterpart and is not subject to this functional inactivation by Pex19p.
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