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Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Nuclear PTEN and p53 suppress stress-induced liver cancer through distinct mechanisms
Takashi Kato1, Daisuke Murata1, Robert A Anders2
1Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
Abstract:
PTEN and p53 are highly mutated in many cancers. These two tumor suppressors have critical functions in the nucleus, such as DNA repair, cell cycle progression, and genome maintenance. However, the in vivo functional relationship of nuclear PTEN and p53 is unknown. Here, we analyzed the liver of mice in which nuclear PTEN and p53 are individually or simultaneously depleted. We found that nuclear PTEN loss greatly upregulates p53 expression upon oxidative stress, while the loss of p53 potentiates stress-induced accumulation of PTEN in the nucleus. Next, we examined oxidative stress-induced DNA damage in hepatocytes, and found that nuclear PTEN loss aggravated the damage while p53 loss did not. Notably, mice lacking nuclear PTEN had increased hepatocellular carcinoma under oxidative stress, while mice lacking p53 in hepatocytes had accelerated hepatocellular carcinoma and intrahepatic cholangiocarcinoma. The formation of cholangiocarcinoma appears to involve the transformation of hepatocytes into cholangiocarcinoma. Simultaneous loss of nuclear PTEN and p53 exacerbated both types of liver cancers. These data suggest that nuclear PTEN and p53 suppress liver cancers through distinct mechanisms.
Insights
Nuclear PTEN and p53 are crucial tumor suppressors. Their loss in liver cells promotes cancer, with PTEN loss worsening DNA damage and p53 loss accelerating liver cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- PTEN (phosphatase and tensin homolog) and p53 are critical tumor suppressors frequently mutated in human cancers.
- Both proteins play vital roles in nuclear functions including DNA repair, cell cycle control, and genome stability.
- The in vivo functional interplay between nuclear PTEN and p53 remains largely uncharacterized.
Purpose of the Study:
- To investigate the functional relationship between nuclear PTEN and p53 in the context of liver cancer development.
- To elucidate the distinct and combined roles of these tumor suppressors in response to oxidative stress and DNA damage in hepatocytes.
Main Methods:
- Analysis of mouse liver models with individual or simultaneous depletion of nuclear PTEN and p53.
- Assessment of p53 expression and PTEN nuclear accumulation under oxidative stress conditions.
- Evaluation of oxidative stress-induced DNA damage in hepatocytes.
- Monitoring the incidence and progression of liver cancers, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma.
Main Results:
- Loss of nuclear PTEN significantly upregulated p53 expression following oxidative stress.
- Loss of p53 enhanced the stress-induced nuclear accumulation of PTEN.
- Nuclear PTEN loss aggravated oxidative stress-induced DNA damage in hepatocytes, whereas p53 loss did not.
- Mice lacking nuclear PTEN exhibited increased hepatocellular carcinoma, while p53-deficient mice showed accelerated hepatocellular carcinoma and intrahepatic cholangiocarcinoma, potentially involving hepatocyte transdifferentiation.
- Simultaneous loss of nuclear PTEN and p53 worsened both cancer types.
Conclusions:
- Nuclear PTEN and p53 act through distinct mechanisms to suppress liver tumorigenesis.
- PTEN's role in DNA damage response and p53's role in tumor suppression are critical for preventing liver cancer.
- Understanding their interplay provides insights into novel therapeutic strategies for liver cancer.
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