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p53-independent apoptosis is induced by the p19ARF tumor suppressor
Keitaro Tsuji1, Kiyohisa Mizumoto, Haruka Sudo
1Department of Pharmacology, KEIO University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Abstract:
p19(ARF) is a potent tumor suppressor. By inactivating Mdm2, p19(ARF) upregulates p53 activities to induce cell cycle arrest and sensitize cells to apoptosis in the presence of collateral signals. It has also been demonstrated that cell cycle arrest is induced by overexpressed p19(ARF) in p53-deficient mouse embryonic fibroblasts, only in the absence of the Mdm2 gene. Here, we show that apoptosis can be induced without additional apoptosis signals by expression of p19(ARF) using an adenovirus-mediated expression system in p53-intact cell lines as well as p53-deficient cell lines. Also, in primary mouse embryonic fibroblasts (MEFs) lacking p53/ARF, p53-independent apoptosis is induced irrespective of Mdm2 status by expression of p19(ARF). In agreement, p19(ARF)-mediated apoptosis in U2OS cells, but not in Saos2 cells, was attenuated by coexpression of Mdm2. We thus conclude that there is a p53-independent pathway for p19(ARF)-induced apoptosis that is insensitive to inhibition by Mdm2.
Insights
The p19(ARF) protein suppresses tumors by inducing apoptosis. This study reveals a p53-independent pathway for p19(ARF)-induced apoptosis that Mdm2 cannot inhibit.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- p19(ARF) is a tumor suppressor that typically upregulates p53 activity.
- p53-dependent cell cycle arrest by p19(ARF) has been observed, particularly in the absence of Mdm2.
- The precise mechanisms of p19(ARF)-induced apoptosis, especially p53-independent pathways, require further elucidation.
Purpose of the Study:
- To investigate the role of p19(ARF) in inducing apoptosis independently of p53.
- To determine if Mdm2 can inhibit p19(ARF)-mediated apoptosis through a p53-independent pathway.
Main Methods:
- Adenovirus-mediated expression of p19(ARF) in various cell lines, including p53-intact and p53-deficient.
- Analysis of apoptosis induction in primary mouse embryonic fibroblasts (MEFs) lacking p53 and ARF.
- Coexpression experiments with Mdm2 in U2OS and Saos2 cells to assess Mdm2's inhibitory effect.
Main Results:
- p19(ARF) expression induced apoptosis in both p53-intact and p53-deficient cell lines without additional apoptotic signals.
- p53-independent apoptosis was observed in p53/ARF-null MEFs, regardless of Mdm2 status.
- Mdm2 coexpression attenuated p19(ARF)-mediated apoptosis in U2OS cells but not in Saos2 cells.
Conclusions:
- A p53-independent pathway exists for p19(ARF)-induced apoptosis.
- This p53-independent apoptotic pathway is resistant to inhibition by Mdm2.