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A network of substrates of the E3 ubiquitin ligases MDM2 and HUWE1 control apoptosis independently of p53.
- Source :
-
Science signaling [Sci Signal] 2013 May 07; Vol. 6 (274), pp. ra32. Date of Electronic Publication: 2013 May 07. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Breast Neoplasms drug therapy
Breast Neoplasms metabolism
Breast Neoplasms pathology
Cell Line, Tumor
Drug Resistance, Neoplasm drug effects
Female
Humans
Imidazoles pharmacology
Immunoblotting
Lapatinib
Mice
Mice, Nude
Myeloid Cell Leukemia Sequence 1 Protein metabolism
Nuclear Proteins metabolism
Phosphoprotein Phosphatases metabolism
Piperazines pharmacology
Protein Kinase Inhibitors pharmacology
Proto-Oncogene Proteins c-mdm2 antagonists & inhibitors
Proto-Oncogene Proteins c-mdm2 genetics
Quinazolines pharmacology
RNA Interference
Receptor, ErbB-2 antagonists & inhibitors
Receptor, ErbB-2 metabolism
Signal Transduction drug effects
Substrate Specificity
Tumor Suppressor Protein p53 genetics
Tumor Suppressor Proteins
Ubiquitin-Protein Ligases genetics
Xenograft Model Antitumor Assays
Apoptosis
Proto-Oncogene Proteins c-mdm2 metabolism
Tumor Suppressor Protein p53 metabolism
Ubiquitin-Protein Ligases metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1937-9145
- Volume :
- 6
- Issue :
- 274
- Database :
- MEDLINE
- Journal :
- Science signaling
- Publication Type :
- Academic Journal
- Accession number :
- 23652204
- Full Text :
- https://doi.org/10.1126/scisignal.2003741