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Abbas, R.* ; Hartmann, O. ; Asiss, D.T.* ; Abbas, R.* ; Kagan, J.* ; Kim, H.T.* ; Oren, M.* ; Diefenbacher, M. ; Orian, A.* ; Larisch, S.*

ARTS and small-molecule ARTS mimetics upregulate p53 levels by promoting the degradation of XIAP.

Apoptosis 29, 1145-1160 (2024)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
Mutations resulting in decreased activity of p53 tumor suppressor protein promote tumorigenesis. P53 protein levels are tightly regulated through the Ubiquitin Proteasome System (UPS). Several E3 ligases were shown to regulate p53 stability, including MDM2. Here we report that the ubiquitin E3 ligase XIAP (X-linked Inhibitors of Apoptosis) is a direct ligase for p53 and describe a novel approach for modulating the levels of p53 by targeting the XIAP pathway. Using in vivo (live-cell) and in vitro (cell-free reconstituted system) ubiquitylation assays, we show that the XIAP-antagonist ARTS regulates the levels of p53 by promoting the degradation of XIAP. XIAP directly binds and ubiquitylates p53. In apoptotic cells, ARTS inhibits the ubiquitylation of p53 by antagonizing XIAP. XIAP knockout MEFs express higher p53 protein levels compared to wild-type MEFs. Computational screen for small molecules with high affinity to the ARTS-binding site within XIAP identified a small-molecule ARTS-mimetic, B3. This compound stimulates apoptosis in a wide range of cancer cells but not normal PBMC (Peripheral Blood Mononuclear Cells). Like ARTS, the B3 compound binds to XIAP and promotes its degradation via the UPS. B3 binding to XIAP stabilizes p53 by disrupting its interaction with XIAP. These results reveal a novel mechanism by which ARTS and p53 regulate each other through an amplification loop to promote apoptosis. Finally, these data suggest that targeting the ARTS binding pocket in XIAP can be used to increase p53 levels as a new strategy for developing anti-cancer therapeutics.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Apoptosis ; Arts ; P53 ; Small-molecules ; Xiap; Programmed Cell-death; Protein Xiap; Apoptosis Proteins; Caspase Activation; Cytochrome-c; Binding-site; Solid Tumors; Inhibitor; Expression; Cancer
ISSN (print) / ISBN 1360-8185
e-ISSN 1573-675X
Zeitschrift Apoptosis
Quellenangaben Band: 29, Heft: 7-8, Seiten: 1145-1160 Artikelnummer: , Supplement: ,
Verlag Springer
Verlagsort Van Godewijckstraat 30, 3311 Gz Dordrecht, Netherlands
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Lung Health and Immunity (LHI)
Förderungen the U.S. Israel Binational Science Foundation Grant
INCPM-ISF
Israel Science Foundation