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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Mitochondrially targeted p53 has tumor suppressor activities in vivo
Flaminia Talos1, Oleksi Petrenko, Patricio Mena
1Department of Pathology, Stony Brook University, Stony Brook, New York 11794-869, USA.
Abstract:
Complex proapoptotic functions are essential for the tumor suppressor activity of p53. We recently described a novel transcription-independent mechanism that involves a rapid proapoptotic action of p53 at the mitochondria and executes the shortest known circuitry of p53 death signaling. Here, we examine if this p53-dependent mitochondrial program could be exploited for tumor suppression in vivo. To test this, we engage Emu-Myc transgenic mice, a well-established model of p53-dependent lymphomagenesis. We show that exclusive delivery of p53 to the outer mitochondrial membrane confers a significant growth disadvantage on Emu-Myc-transformed B-cells of p53-deficient or alternate reading frame-deficient genotypes, resulting in efficient induction of apoptosis and impinged proliferation. Conversely, normal cells from thymus, spleen, and bone marrow showed poor infectivity with these viruses. This proof-of-principle experiment shows that exclusive reliance on the direct mitochondrial program exerts a significant tumor suppressor activity in vivo. Our in vivo data on the direct mitochondrial apoptotic p53 program lays the groundwork to further investigate its efficacy and safety and to address its possible therapeutic value in the future.
Insights
Targeting mitochondria with p53 triggers apoptosis in cancer cells. This novel approach shows significant tumor suppressor activity in vivo, offering potential for future cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- The tumor suppressor protein p53 (also known as TP53) plays a critical role in preventing cancer through complex proapoptotic functions.
- A novel transcription-independent mechanism of p53 involves rapid proapoptotic action at the mitochondria, representing the shortest known p53 death signaling pathway.
Purpose of the Study:
- To investigate the potential of exploiting the p53-dependent mitochondrial apoptotic program for in vivo tumor suppression.
- To evaluate the efficacy of targeted mitochondrial delivery of p53 in a mouse model of lymphomagenesis.
Main Methods:
- Utilized Emu-Myc transgenic mice, a model for p53-dependent lymphomagenesis.
- Engineered exclusive delivery of p53 to the outer mitochondrial membrane.
- Assessed the impact on Emu-Myc-transformed B-cells and normal cells from thymus, spleen, and bone marrow.
Main Results:
- Exclusive mitochondrial delivery of p53 significantly inhibited the proliferation of Emu-Myc-transformed B-cells from p53-deficient or alternate reading frame-deficient mice.
- This targeted approach efficiently induced apoptosis and impinged proliferation in cancer cells.
- Normal cells exhibited poor infectivity with the engineered viruses, indicating specificity.
Conclusions:
- The direct mitochondrial apoptotic p53 program demonstrates significant tumor suppressor activity in vivo.
- This proof-of-principle study supports further investigation into the therapeutic potential and safety of this novel cancer treatment strategy.
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