mdm2 Is Critical for Inhibition of p53 during Lymphopoiesis and the Response to Ionizing Irradiation

Mendrysa, Susan M.; McElwee, Matthew K.; Michalowski, Jennifer; O'Leary, Kathleen A.; Young, Karen M.; Perry, Mary Ellen

doi:10.1128/mcb.23.2.462-473.2003

Cited by 234Cancer-related Molecular PathwaysCell death mechanisms and regulationHeat shock proteins research

mdm2 Is Critical for Inhibition of p53 during Lymphopoiesis and the Response to Ionizing Irradiation

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Mendrysa, Susan M., McElwee, Matthew K., Michalowski, Jennifer, O'Leary, Kathleen A., Young, Karen M., Perry, Mary Ellen·2003·Molecular and Cellular Biology

DOI 10.1128/mcb.23.2.462-473.2003PMC PMC151546

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Abstract

The function of the p53 tumor suppressor protein must be highly regulated because p53 can cause cell death and prevent tumorigenesis. In cultured cells, the p90MDM2 protein blocks the transcriptional activation domain of p53 and also stimulates the degradation of p53. Here we provide the first conclusive demonstration that p90MDM2 constitutively regulates p53 activity in homeostatic tissues. Mice with a hypomorphic allele of mdm2 revealed a heretofore unknown role for mdm2 in lymphopoiesis and epithelial cell survival. Phenotypic analyses revealed that both the transcriptional activation and apoptotic functions of p53 were increased in these mice. However, the level of p53 protein was not coordinately increased, suggesting that p90MDM2 can inhibit the transcriptional activation and apoptotic functions of p53 in a manner independent of degradation. Cre-mediated deletion of mdm2 caused a greater accumulation of p53, demonstrating that p90MDM2 constitutively regulates both the activity and the level of p53 in homeostatic tissues. The observation that only a subset of tissues with activated p53 underwent apoptosis indicates that factors other than p90(MDM2) determine the physiological consequences of p53 activation. Furthermore, reduction of mdm2 in vivo resulted in radiosensitivity, highlighting the importance of mdm2 as a potential target for adjuvant cancer therapies.

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Mice with one hypomorphic and one null Mdm2 allele express about 30% of wild-type Mdm2, have increased p53 activity, and are small, lymphopenic, and radiosensitive.
“Moreover, mice carrying a hypomorphic and a null allele of Mdm2, which express about 30% of wild-type Mdm2 levels, have increased p53 activity and are small, lymphopenic, and radiosensitive (Mendrysa, et al., 2003).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Mendrysa, et al., 2003

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Authors: Mendrysa, S. M., McElwee, M. K., Michalowski, J., O'Leary, K. A., Young, K. M., & Perry, M. E.
Affiliations: University of Wisconsin System (US)
Department of Oncology, School of Medicine
National Institutes of Health (US)
University of Wisconsin–Madison (US)
ORCID: McElwee, Matthew K.
Perry, Mary Ellen
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 2003-01
Volume: 23
Issue: 2
Pages: 462-472
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.23.2.462-473.2003
PMC: PMC151546
OpenAlex: W2130555878
Cited by: 234
References: 61
Citations by year: 2026: 2 · 2025: 1 · 2024: 4 · 2023: 6 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 8 · 2018: 5 · 2017: 7 · 2016: 16 · 2015: 6 · 2014: 14 · 2013: 7 · 2012: 20
FWCI: 5.03
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5p30ca007175-36)
National Cancer Institute (CA-07175, CA14520, T32CA009135, CA-70718, CA09135, P30CA014520)
National Institute of General Medical Sciences (GM 07215, T32GM007215)
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords: MDM2, p53, lymphocyte development, ionizing radiation, radiosensitivity, p53 transcriptional activation, p53-dependent apoptosis, epithelial cell survival, p53 degradation, tumor suppressor regulation, adjuvant cancer therapy
MeSH terms: Alleles, Animals, Body Weight, Cells, Cultured, Dose-Response Relationship, Radiation, Flow Cytometry, Genotype, Hematopoietic Stem Cells, Lymphocytes, Mice, Inbred C57BL, Mice, Transgenic, Models, Genetic, Nuclear Proteins, Precipitin Tests, Proto-Oncogene Proteins, RNA, Messenger, Time Factors, Tissue Distribution, Transcription, Genetic, Blotting, Northern, Blotting, Western, Transcriptional Activation, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Cell Death, Apoptosis, Gene Deletion, Protein Structure, Tertiary, In Situ Nick-End Labeling, Mice, Proto-Oncogene Proteins c-mdm2

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mdm2 Is Critical for Inhibition of p53 during Lymphopoiesis and the Response to Ionizing Irradiation

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