A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.
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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.
Cell Line, Tumor
Drug Resistance, Neoplasm
Myeloid Cell Leukemia Sequence 1 Protein
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-mdm2
Tumor Suppressor Protein p53
Xenograft Model Antitumor Assays
Published Version (Please cite this version)10.1126/scisignal.2003741
Publication InfoDewhirst, Mark Wesley; Geradts, J; Henao, R; Kim, J; Kim, WJ; Kornbluth, S; ... Xia, W (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 http://hdl.handle.net/10161/8398.
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Gustavo S. Montana Professor of Radiation Oncology, in the School of Medicine
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
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.
Jo Rae Wright University Professor
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
Associate Research Professor in the Social Science Research Institute
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