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Updated: Aug 16, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
Suppression of p53 by Notch in lymphomagenesis: implications for initiation and regression
Levi J Beverly1, Dean W Felsher, Anthony J Capobianco
1The Wistar Institute, Philadelphia, Pennsylvania 19104, USA.
Abstract:
Aberrant Notch signaling contributes to more than half of all human T-cell leukemias, and accumulating evidence indicates Notch involvement in other human neoplasms. We developed a tetracycline-inducible mouse model (Top-Notch(ic)) to examine the genetic interactions underlying the development of Notch-induced neoplastic disease. Using this model, we show that Notch suppresses p53 in lymphomagenesis through repression of the ARF-mdm2-p53 tumor surveillance network. Attenuation of Notch expression resulted in a dramatic increase in p53 levels that led to tumor regression by an apoptotic program. This shows that continued Notch activity is required to maintain the disease state. However, all tumors relapsed with rapid kinetics, most of which, by reactivation of Notch expression. Furthermore, by directly inhibiting the mdm2-p53 interaction by using either ionizing radiation or the novel small molecule therapeutic Nutlin, p53 can be activated and cause tumor cell death, even in the presence of sustained Notch activity. Therefore, it is the suppression of p53 that provides the Achilles heel for Notch-induced tumors, as activation of p53 in the presence of Notch signaling drives tumor regression. Our study provides proof-of-principle for the rational targeting of therapeutics against the mdm2-p53 pathway in Notch-induced neoplasms. Furthermore, we propose that suppression of p53 by Notch is a key mechanism underlying the initiation of T-cell lymphoma.
Insights
Aberrant Notch signaling drives T-cell leukemia by suppressing the p53 tumor suppressor. Reactivating p53 triggers tumor regression, offering a therapeutic target for Notch-induced neoplasms.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Aberrant Notch signaling is implicated in over 50% of human T-cell leukemias and other neoplasms.
- Notch signaling's role in tumorigenesis is increasingly recognized, necessitating further investigation into its underlying mechanisms.
Purpose of the Study:
- To investigate the genetic interactions in Notch-induced neoplastic disease using a novel tetracycline-inducible mouse model (Top-Notch(ic)).
- To elucidate the mechanism by which Notch signaling contributes to lymphomagenesis and identify potential therapeutic vulnerabilities.
Main Methods:
- Development of a tetracycline-inducible mouse model (Top-Notch(ic)) to control Notch expression.
- Analysis of the ARF-mdm2-p53 tumor surveillance network in Notch-induced lymphomagenesis.
- Evaluation of therapeutic strategies involving ionizing radiation and Nutlin to inhibit the mdm2-p53 interaction.
Main Results:
- Notch signaling suppresses p53 through repression of the ARF-mdm2-p53 network, maintaining the disease state.
- Attenuation of Notch expression leads to p53 upregulation and tumor regression via apoptosis.
- Tumors relapsed upon Notch expression reactivation, but direct mdm2-p53 inhibition with radiation or Nutlin induced tumor cell death despite sustained Notch activity.
Conclusions:
- Suppression of p53 is a critical Achilles' heel in Notch-induced tumors.
- Activation of p53, even in the presence of Notch signaling, drives tumor regression.
- Targeting the mdm2-p53 pathway presents a rational therapeutic strategy for Notch-induced neoplasms, particularly T-cell lymphoma.
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