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A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.

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Date
2013-05-07
Authors
Kurokawa, Manabu
Kim, Jiyeon
Geradts, Joseph
Matsuura, Kenkyo
Liu, Liu
Ran, Xu
Xia, Wenle
Ribar, Thomas J
Henao, Ricardo
Dewhirst, Mark W
Kim, Wun-Jae
Lucas, Joseph E
Wang, Shaomeng
Spector, Neil L
Kornbluth, Sally
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(15 total)
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Abstract
In the intrinsic pathway of apoptosis, cell-damaging signals promote the release of cytochrome c from mitochondria, triggering activation of the Apaf-1 and caspase-9 apoptosome. The ubiquitin E3 ligase MDM2 decreases the stability of the proapoptotic factor p53. We show that it also coordinated apoptotic events in a p53-independent manner by ubiquitylating the apoptosome activator CAS and the ubiquitin E3 ligase HUWE1. HUWE1 ubiquitylates the antiapoptotic factor Mcl-1, and we found that HUWE1 also ubiquitylated PP5 (protein phosphatase 5), which indirectly inhibited apoptosome activation. Breast cancers that are positive for the tyrosine receptor kinase HER2 (human epidermal growth factor receptor 2) tend to be highly aggressive. In HER2-positive breast cancer cells treated with the HER2 tyrosine kinase inhibitor lapatinib, MDM2 was degraded and HUWE1 was stabilized. In contrast, in breast cancer cells that acquired resistance to lapatinib, the abundance of MDM2 was not decreased and HUWE1 was degraded, which inhibited apoptosis, regardless of p53 status. MDM2 inhibition overcame lapatinib resistance in cells with either wild-type or mutant p53 and in xenograft models. These findings demonstrate broader, p53-independent roles for MDM2 and HUWE1 in apoptosis and specifically suggest the potential for therapy directed against MDM2 to overcome lapatinib resistance.
Type
Journal article
Subject
Animals
Apoptosis
Breast Neoplasms
Cell Line, Tumor
Drug Resistance, Neoplasm
Female
Humans
Imidazoles
Immunoblotting
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein
Nuclear Proteins
Phosphoprotein Phosphatases
Piperazines
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-mdm2
Quinazolines
RNA Interference
Receptor, ErbB-2
Signal Transduction
Substrate Specificity
Tumor Suppressor Protein p53
Ubiquitin-Protein Ligases
Xenograft Model Antitumor Assays
Permalink
https://hdl.handle.net/10161/8398
Published Version (Please cite this version)
10.1126/scisignal.2003741
Publication Info
Kurokawa, Manabu; Kim, Jiyeon; Geradts, Joseph; Matsuura, Kenkyo; Liu, Liu; Ran, Xu; ... Kornbluth, Sally (2013). A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53. Sci Signal, 6(274). pp. ra32. 10.1126/scisignal.2003741. Retrieved from https://hdl.handle.net/10161/8398.
This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.
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Scholars@Duke

Dewhirst

Mark Wesley Dewhirst

Gustavo S. Montana Distinguished Professor Emeritus of Radiation Oncology
Mark W. Dewhirst, DVM, PhD is the Gustavo S. Montana Professor of Radiation Oncology and Vice Director for Basic Science in the Duke Cancer Institute. Dr. Dewhirst has research interests in tumor hypoxia, angiogenesis, hyperthermia and drug transport. He has spent 30 years studying causes of tumor hypoxia and the use of hyperthermia to treat cancer. In collaboration with Professor David Needham in the Pratt School of Engineering, he has developed a novel thermally sensitive drug carrying liposom
Geradts

Joseph Geradts

Adjunct Professor in the Department of Pathology
Dr. Geradts' primary research focus is on the molecular pathology of breast cancer. His laboratory uses genomic profiling strategies to identify novel candidate breast cancer genes. Dr. Geradts is also interested in biomarker development. He directs the Tissue Core of Duke's Breast Cancer SPORE and collaborates on numerous breast cancer related research projects with other investigators at Duke and elsewhere.
Henao

Ricardo Henao

Associate Professor in Biostatistics & Bioinformatics
Kornbluth

Sally A. Kornbluth

Jo Rae Wright University Distinguished Professor Emerita
Our lab studies the regulation of complex cellular processes, including cell cycle progression and programmed cell death (apoptosis). These tightly orchestrated processes are critical for appropriate cell proliferation and cell death, and when they go awry can result in cancer and degenerative disorders. Within these larger fields, we have focused on understanding the cellular mechanisms that prevent the onset of mitosis prior to the completion of DNA replication, the process
Lucas

Joseph E. Lucas

Associate Research Professor in the Social Science Research Institute
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
Spector

Neil Lee Spector

Sandra Coates Associate Professor
This author no longer has a Scholars@Duke profile, so the information shown here reflects their Duke status at the time this item was deposited.
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Alphabetical list of authors with Scholars@Duke profiles.
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