Abstract
The p53 tumor suppressor protein is regulated by its interaction with HDM2, which serves as a ubiquitin ligase (E3) to target p53 for degradation. We have identified a family of small molecules (HLI98) that inhibits HDM2's E3 activity. These compounds show some specificity for HDM2 in vitro, although at higher concentrations effects on unrelated RING and HECT domain E3s are detectable, which could be due, at least in part, to effects on E2-ubiquitin thiol-ester levels. In cells, the compounds allow the stabilization of p53 and HDM2 and activation of p53-dependent transcription and apoptosis, although other p53-independent toxicity was also observed.
MeSH Terms
Animals
Apoptosis/drug effects
Caspases/metabolism
Cell Cycle Proteins/metabolism
Cell Line
Cell Line, Tumor
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase Inhibitor p21
Cyclin-Dependent Kinases/metabolism
Endosomal Sorting Complexes Required for Transport
Enzyme Inhibitors/chemistry,pharmacology
Epithelial Cells/drug effects,metabolism
Fibroblasts/drug effects,metabolism
Flavins/chemistry
Gene Expression/drug effects
Humans
Mice
Molecular Structure
Nedd4 Ubiquitin Protein Ligases
Nuclear Proteins/antagonists & inhibitors,genetics,metabolism
Phosphorylation/drug effects
Poly(ADP-ribose) Polymerases/metabolism
Protein Binding/drug effects
Proteins/antagonists & inhibitors,metabolism
Proto-Oncogene Proteins/antagonists & inhibitors,genetics,metabolism
Proto-Oncogene Proteins c-mdm2
Transfection
Tumor Suppressor Protein p53/genetics,metabolism
Ubiquitin/metabolism
Ubiquitin-Protein Ligases/antagonists & inhibitors,metabolism
Chemicals
CDKN1A protein, human
Cdkn1a protein, mouse
Cell Cycle Proteins
Cyclin-Dependent Kinase Inhibitor p21
Endosomal Sorting Complexes Required for Transport
Enzyme Inhibitors
Flavins
Nuclear Proteins
Proteins
Proto-Oncogene Proteins
Tumor Suppressor Protein p53
Ubiquitin
5-deazaflavin
Nedd4 Ubiquitin Protein Ligases
UBE3A protein, human
MDM2 protein, human
Mdm2 protein, mouse
Proto-Oncogene Proteins c-mdm2
Ubiquitin-Protein Ligases
seven in absentia proteins
Poly(ADP-ribose) Polymerases
CDK4 protein, human
Cdk4 protein, mouse
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinases
Caspases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Yang Yili
Laboratory of Protein Dynamics and Signaling, Center for Cancer Research, National Cancer Institute at Frederick, NIH, 1050 Boyles Street, Frederick, MD 21702, USA.
Ludwig Robert L
Jensen Jane P
Pierre Shervon A
Medaglia Maxine V
Davydov Ilia V
Safiran Yassamin J
Oberoi Pankaj
Kenten John H
Phillips Andrew C
Weissman Allan M
Vousden Karen H
