Naslov
The interplay between p63/p73 and mutant p53 might be influenced by E3 ubiquitin ligase ITCH

Autori
Zorić, Arijana ; Horvat, Anđela, Pfeiffer, Anamarija ; Slade, Neda

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Izvornik
8th Interanational MDM2 Workshop / - New Orleans (LA), 2015

Skup
8th Interanational MDM2 Workshop

Mjesto i datum
New Orleans (LA), Sjedinjene Američke Države, 01.11.2015. - 04.11.2015

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
mutant p53; p63; p73; ITCH

Sažetak
To understand the p53 pathways all three p53 family members have to be taken into account. p73 and p63 were shown to activate many p53 target genes, both are able to induce cell cycle arrest and apoptosis and are activated upon DNA damage. N-terminally truncated forms (ΔNp73/ ΔNp63) can act as potential transdominant inhibitors of TAp73, TAp63 (transactivation competent forms) and wild type p53. While TP73 and TP63 are rarely mutated in tumors, TP53 is mutated in many tumors losing its tumor suppressor functions, and often gaining oncogenic functions that stimulate tumor progression. Some of the mutant p53 oncogenic features are explained through interactions with other p53 family members, specifically tumor suppressor isoforms TAp63 and TAp73. Some mutants show strong binding to both TAp73β and TAp63α (R175H, L194F, R282W) while R280K weekly binds. Consequently, R280K does not inhibit transcriptional activity of TAp73β comparing to other mutants. It is established that p73 protein stability is predominantly regulated by Itch, HECT domain E3 ubiquitin ligase, which ubiquitinates p73 and targets it to proteosomal degradation. Since it was found that MDM2 functionally affects the relationship between p63/p73 and mutant p53, we assume that Itch could affect mutant p53/TAp73β and mutant p53/ TAp63α interaction. We have found that Itch inhibits the binding of all mutants to TAp73β what is the consequence of TAp73β proteasomal degradation. However, as was observed by western blot upon transfection of TAp73β and p53 mutants L194F and R280K, the expression of TAp73β was not affected by Itch. Deeper understanding of the interplay between Itch and mutant p53-p63/p73 may provide another new to target the activity of mutant p53.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti

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