Cited by 357Cancer-related Molecular PathwaysProtein Kinase Regulation and GTPase SignalingCell death mechanisms and regulation

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Opposing Effects of Ras on p53

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Ries, Stefan, Biederer, Carola, Woods, Douglas, Shifman, Ohad, Shirasawa, Senji, Sasazuki, Takehiko, McMahon, Martin, Oren, Moshe, McCormick, Frank·2000·Cell

DOI 10.1016/s0092-8674(00)00123-9

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Abstract

Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.

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Authors: Ries, S., Biederer, C., Woods, D., Shifman, O., Shirasawa, S., Sasazuki, T., McMahon, M., Oren, M., & McCormick, F.
Affiliations: University of California, San Francisco (US)
Weizmann Institute of Science (IL)
Kyushu University (JP)
Corresponding author: McCormick, Frank
ORCID: Ries, Stefan
Shifman, Ohad
Shirasawa, Senji
Sasazuki, Takehiko
McMahon, Martin
Oren, Moshe
McCormick, Frank
Venue: Cell
Publisher: Elsevier BV
Published: 2000-10
Volume: 103
Issue: 2
Pages: 321-330
ISSN: 0092-8674 (ISSN-L)
DOI: 10.1016/s0092-8674(00)00123-9
OpenAlex: W2022614681
Cited by: 357
References: 75
Citations by year: 2026: 1 · 2025: 5 · 2024: 5 · 2023: 2 · 2022: 4 · 2021: 8 · 2020: 10 · 2019: 4 · 2018: 6 · 2017: 5 · 2016: 10 · 2015: 7 · 2014: 16 · 2013: 9 · 2012: 17
FWCI: 13.36
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 4672 d)
Locations: Cell (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Keywords: Ras, p53, MDM2, p19ARF, p53 degradation, p53-dependent apoptosis, DNA damage resistance, oncogenic Ras, tumor suppression
MeSH terms: Animals, Base Sequence, Cell Line, Gamma Rays, Mice, Mutant Strains, Molecular Sequence Data, Mutagens, Mutation, Nuclear Proteins, Promoter Regions, Genetic, Proteins, Proto-Oncogene Proteins, Radiation Tolerance, Transcription Factors, Signal Transduction, Tumor Suppressor Protein p53, ras Proteins, Transcription Factor AP-1, Proto-Oncogene Proteins c-raf, Response Elements, Tumor Suppressor Protein p14ARF, Proto-Oncogene Proteins c-ets, Mice, Proto-Oncogene Proteins c-mdm2

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