Suppression of p53 by Notch in lymphomagenesis: Implications for initiation and regression

Levi J. Beverly, Dean W. Felsher, Anthony J Capobianco

Research output: Contribution to journalArticle

124 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7159-7168
Number of pages10
JournalCancer Research
Volume65
Issue number16
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

Fingerprint

Neoplasms
T-Cell Leukemia
T-Cell Lymphoma
Ionizing Radiation
Tetracycline
Cell Death
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Suppression of p53 by Notch in lymphomagenesis : Implications for initiation and regression. / Beverly, Levi J.; Felsher, Dean W.; Capobianco, Anthony J.

In: Cancer Research, Vol. 65, No. 16, 15.08.2005, p. 7159-7168.

Research output: Contribution to journalArticle

@article{7f7df17cba3b4431a714ead8054b3dd1,
title = "Suppression of p53 by Notch in lymphomagenesis: Implications for initiation and regression",
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.",
author = "Beverly, {Levi J.} and Felsher, {Dean W.} and Capobianco, {Anthony J}",
year = "2005",
month = "8",
day = "15",
doi = "10.1158/0008-5472.CAN-05-1664",
language = "English",
volume = "65",
pages = "7159--7168",
journal = "Journal of Cancer Research",
issn = "0099-7013",
publisher = "American Association for Cancer Research Inc.",
number = "16",

}

TY - JOUR

T1 - Suppression of p53 by Notch in lymphomagenesis

T2 - Implications for initiation and regression

AU - Beverly, Levi J.

AU - Felsher, Dean W.

AU - Capobianco, Anthony J

PY - 2005/8/15

Y1 - 2005/8/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=23844446044&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=23844446044&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-1664

DO - 10.1158/0008-5472.CAN-05-1664

M3 - Article

C2 - 16103066

AN - SCOPUS:23844446044

VL - 65

SP - 7159

EP - 7168

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0099-7013

IS - 16

ER -