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

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

United States

2014-03-13T16:10:39Z

2013-05-07

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.

http://www.ncbi.nlm.nih.gov/pubmed/23652204

6/274/ra32

1937-9145

https://hdl.handle.net/10161/8398

eng

American Association for the Advancement of Science (AAAS)

Sci Signal

10.1126/scisignal.2003741

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

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

Journal article

Henao, Ricardo|0000-0003-4980-845X

Dewhirst, Mark W|0000-0003-3459-6546

http://www.ncbi.nlm.nih.gov/pubmed/23652204

ra32

274

Basic Science Departments

Biomedical Engineering

Biostatistics & Bioinformatics

Clinical Science Departments

Duke

Duke Cancer Institute

Electrical and Computer Engineering

Faculty

Institutes and Centers

Institutes and Provost's Academic Units

Medicine

Medicine, Medical Oncology

Pathology

Pharmacology & Cancer Biology

Pratt School of Engineering

Radiation Oncology

School of Medicine

Social Science Research Institute

University Institutes and Centers

Published online

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