A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.
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 articleSubject
AnimalsApoptosis
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
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https://hdl.handle.net/10161/8398Published Version (Please cite this version)
10.1126/scisignal.2003741Publication 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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Show full item recordScholars@Duke
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
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.
Ricardo Henao
Associate Professor in Biostatistics & Bioinformatics
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
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.
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.
Alphabetical list of authors with Scholars@Duke profiles.

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