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Contribution of the dual coding capacity of the p16INK4a/MTS1/CDKN2 locus to human malignancies
1INSERM U-301, Institut de Génétique Moléculaire, Paris, France.
Abstract:
During the three last years, the so-called p16 locus on human chromosome band 9p21 has been increasingly implicated in different cancers by a variety of alterations abolishing both copies of the p16INK4a/MTS1/CDKN2 gene and the adjacent p15INK4b gene, two members of a family of specific inhibitors of the cyclin D 1-3-CDK4/6 complexes that control cell cycle progression of the G1 to S phase. While these properties are characteristic of tumor suppressor genes, abundant experimental data have clearly identified a link between the loss of function of p16INK4a and tumorigenic processes. The role of p15INK4b alterations in the onset of natural and experimental tumors is less obvious. New light may be shed on the role of the p16 locus in tumor development by the recent finding that an alternative transcript from the p16INK4a gene encodes p19ARF, a negative regulator of cell cycle progression which is unrelated to p16 and p15 and does not act by binding any CDK. Hence, this protein appears to be an element of a novel negative cell cycle control mechanism, whose impairing might be involved in tumorigenesis.
Insights
Alterations in the p16 locus, including the p16INK4a gene, are linked to cancer development. A newly identified protein, p19ARF, from the p16INK4a gene may also play a role in tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The p16 locus on human chromosome 9p21 is frequently altered in various cancers.
- Alterations affect both p16INK4a/MTS1/CDKN2 and p15INK4b genes, inhibitors of cyclin D-CDK4/6 complexes controlling G1 to S phase cell cycle progression.
Purpose of the Study:
- To investigate the role of the p16 locus, including p16INK4a and p15INK4b, in cancer development.
- To explore the potential involvement of the p19ARF protein, encoded by an alternative p16INK4a transcript, in tumorigenesis.
Main Methods:
- Analysis of alterations in the p16 locus in cancer samples.
- Investigation of the function of p16INK4a, p15INK4b, and p19ARF in cell cycle regulation.
Main Results:
- Loss of function of p16INK4a is strongly associated with tumorigenic processes.
- The role of p15INK4b alterations in tumor development is less clear.
- p19ARF, a novel cell cycle regulator, is encoded by an alternative p16INK4a transcript and does not interact with CDKs.
Conclusions:
- The p16INK4a gene and its product p19ARF are critical in cell cycle control and tumor suppression.
- Impairment of this novel regulatory mechanism involving p19ARF may contribute to cancer development.