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Published on: April 5, 2018
[Clearing up the p16INK4a-p14/p19ARF imbroglio?]
1Laboratoire d'oncologie moléculaire, IBMIG, 40, avenue du Recteur-Pineau, 86022, Poitiers. c.j.larsen@chu-poitiers.fr
Abstract:
Since its discovery, the CDKN2/MTS1 locus has been considered as an important site for the understanding of cell cycle deregulations that are involved in cancer cell generation. A comprehensive approach of the respective roles played by the two p16INK4a and p14/p19ARF (ARF) proteins encoded by this locus was not yet achieved because of the structural intrication of their genes. Inactivation of the only p16INK4a gene in mouse allowed to get better insight into this puzzle. In vivo results presented by de Pinho's group showed that inactivation of both p16INK4a alleles generated a panel of various types of tumors from the 28th week following birth. Bern's group dit not confirm this result but showed that the presence of only one ARF functional copy increases sensitivity of p16-/- mice to tumor occurrence indicating that insufficient dosage of ARF protein may facilitate tumorigenesis. It seems now established that, at least in mouse, ARF controls senescence in vitro, immortalisation and transformation by oncogenic ras. p16INK4a inactivation appears to be crucial for the induction of carcinogens-induced tumors.
Insights
The CDKN2/MTS1 locus is key to understanding cancer. In mice, inactivating p16INK4a is vital for carcinogen-induced tumors, while insufficient ARF protein dosage may also promote tumorigenesis.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The CDKN2/MTS1 locus is critical for understanding cell cycle deregulation in cancer.
- The distinct roles of p16INK4a and p14/p19ARF (ARF) proteins from this locus are complex due to gene structure.
- Previous studies have not fully elucidated the combined functions of p16INK4a and ARF.
Purpose of the Study:
- To investigate the specific roles of p16INK4a and ARF proteins in tumor development.
- To clarify the contribution of p16INK4a inactivation to carcinogen-induced tumors.
- To assess the impact of ARF dosage on tumor susceptibility in mice.
Main Methods:
- Inactivation of the p16INK4a gene in mouse models.
- Analysis of tumor development in mice with altered p16INK4a and ARF gene status.
- In vitro studies on senescence, immortalization, and oncogenic ras transformation.
Main Results:
- Inactivation of both p16INK4a alleles in mice led to various tumors.
- Reduced functional copies of ARF increased tumor susceptibility in p16INK4a-deficient mice.
- ARF controls senescence, immortalization, and ras-driven transformation in vitro.
- p16INK4a inactivation is essential for carcinogen-induced tumor formation.
Conclusions:
- p16INK4a inactivation is crucial for carcinogen-induced tumorigenesis in mice.
- ARF plays a significant role in tumor suppression, with dosage affecting susceptibility.
- Understanding the interplay between p16INK4a and ARF is vital for cancer research.
