title: Proteasome inhibitors suppress the protein expression of mutant p53.
abstract: Tumor suppressor p53 is one of the most frequently mutated genes in cancer, with almost 50% of all types of cancer expressing a mutant form of p53. p53 transactivates the expression of its primary negative regulator, HDM2. HDM2 is a ubiquitin ligase, which initiates the proteasomal degradation of p53 following ubiquitination. Proteasome inhibitors, by targeting the ubiquitin proteasome pathway inhibit the degradation of the majority of cellular proteins including wild-type p53. In contrast, in this study we found that the protein expression of mutant p53 was suppressed following treatment with established or novel proteasome inhibitors. Furthermore, for the first time we demonstrated that Arsenic trioxide, which was previously shown to suppress mutant p53 protein level, exhibits proteasome inhibitory activity. Proteasome inhibitor-mediated suppression of mutant p53 was partially rescued by the knockdown of HDM2, suggesting that the stabilization of HDM2 by proteasome inhibitors might be responsible for mutant p53 suppression to some extent. This study suggests that suppression of mutant p53 is a general property of proteasome inhibitors and it provides additional rationale to use proteasome inhibitors for the treatment of tumors with mutant p53.
authors.affiliation: a Department of Medicine ; University of Illinois at Chicago ; Chicago , IL USA.
authors.forename: Marianna
authors.initials: M
authors.lastname: Halasi
authors.forename: Bulbul
authors.initials: B
authors.lastname: Pandit
authors.forename: Andrei L
authors.initials: AL
authors.lastname: Gartel
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D045744:Cell Line, Tumor; D006801:Humans; D010087:Oxides / Q000494:pharmacology; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D001152:Arsenicals; D010087:Oxides; D061988:Proteasome Inhibitors; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide; Bax, Bcl-2-associated X; Bcl-2, B-cell lymphoma 2; FOXM1, Forkhead Box M1, Mcl-1, Myeloid cell leukemia sequence 1; HDM2; HDM2, human double minute 2; PUMA, p53 upregulated modulator of apoptosis; RNAi; p53; proteasome inhibitors