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A major functional difference between the mouse and human ARF tumor suppressor proteins
Renu Wadhwa1, Takashi Sugihara, Md Kamrul Hasan
1Gene Function Research Laboratory, Research Center for Glycoscience, National Institute of Advanced Industrial Science and Technology (AIST), 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566, Japan.
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.
Insights
Human tumor suppression is more effective than in mice due to differences in the alternative reading frame (ARF) protein. Mouse ARF (p19ARF) is inactivated by Pex19p, while human ARF (p14ARF) is not, impacting p53 function.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Tumorigenesis suppression is more robust in humans than mice, with underlying reasons unclear.
- The alternative reading frame (ARF) protein, encoded with p16(INK4a), is a key tumor suppressor upstream of p53.
- Significant divergence exists between mouse and human ARF proteins, particularly at their carboxyl termini.
Purpose of the Study:
- To investigate functional distinctions in the regulation of mouse (p19ARF) and human (p14ARF) proteins.
- To elucidate the role of Pex19p in the cytoplasmic localization and inactivation of p19ARF.
- To compare the functional consequences of Pex19p interaction on p19ARF and p14ARF in a shared cellular context.
Main Methods:
- Comparative analysis of mouse p19ARF and human p14ARF protein structures and functions.
- Investigated the interaction between p19ARF and Pex19p in cellular cytoplasm.
- Utilized ribozymes targeting Pex19p to assess its impact on ARF-mediated p53 activation.
Main Results:
- Mouse p19ARF interacts with Pex19p, leading to cytoplasmic sequestration and impaired p53 activation.
- Human p14ARF, being smaller, does not undergo inactivation by Pex19p.
- Targeting Pex19p with ribozymes enhanced p19ARF-mediated p53 function but not p14ARF-mediated function.
Conclusions:
- Demonstrated a novel functional difference between mouse and human ARF proteins.
- Pex19p-mediated inactivation of p19ARF represents a species-specific regulatory mechanism.
- This ARF functional distinction may contribute to the differing tumor proneness observed between humans and mice.