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Sci. Signal., 7 May 2013
Vol. 6, Issue 274, p. ra32
[DOI: 10.1126/scisignal.2003741]

RESEARCH ARTICLES

A Network of Substrates of the E3 Ubiquitin Ligases MDM2 and HUWE1 Control Apoptosis Independently of p53

Manabu Kurokawa1*, Jiyeon Kim2{dagger}, Joseph Geradts3, Kenkyo Matsuura2, Liu Liu4, Xu Ran4, Wenle Xia5, Thomas J. Ribar2, Ricardo Henao6, Mark W. Dewhirst7, Wun-Jae Kim8, Joseph E. Lucas6, Shaomeng Wang4, Neil L. Spector5, and Sally Kornbluth2*

1 Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
2 Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
3 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA.
4 Comprehensive Cancer Center, Department of Internal Medicine, and Department of Medicinal Chemistry, University of Michigan, Ann Arbor, MI 48109, USA.
5 Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
6 Institute for Genome Sciences and Policy, Duke University Medical Center, Durham, NC 27710, USA.
7 Department of Radiation Oncology, Duke University Medical Center, Durham, NC 27710, USA.
8 Department of Urology, College of Medicine, Chungbuk National University, Cheongju, Chungbuk 361-711, Korea.

{dagger} Present address: Children’s Medical Center Research Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390–8502, USA.

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.

* Corresponding author. E-mail: manabu.kurokawa{at}dartmouth.edu (M.K.); sally.kornbluth{at}duke.edu (S.K.)

Citation: M. Kurokawa, J. Kim, J. Geradts, K. Matsuura, L. Liu, X. Ran, W. Xia, T. J. Ribar, R. Henao, M. W. Dewhirst, W.-J. Kim, J. E. Lucas, S. Wang, N. L. Spector, S. Kornbluth, A Network of Substrates of the E3 Ubiquitin Ligases MDM2 and HUWE1 Control Apoptosis Independently of p53. Sci. Signal. 6, ra32 (2013).

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