Cooperation of p300 and iASPP in apoptosis and tumour suppression

摘要: Mutation or functional inactivation of tumour suppressors represents a key event in the transformation cells and contributes to development cancer. P300 CBP constitute two histone acetyltransferases with suppressor functions that are frequently mutated inactivated Accordingly, after chemotherapy-induced DNA damage, for example, p300 can co-activate proteins p53 TAp73, thereby contributing cell apoptosis. Here we investigated impact co-factor protein iASPP on TAp73 function, treatment tumourigenic lines chemotherapeutic drug cisplatin. belongs ASPP-family, another class co-factors contribute p53-family-mediated apoptosis induction. Direct interaction has been revealed before; consequences these interactions remain elusive though therefore subject our analyses. By investigating stable knockdown lines, found direct cisplatin-treated led enhanced stability TAp73. Correspondingly, depletion resulted decreased amounts p300, reduced induction pro-apoptotic p73 target genes impaired apoptosis. BRMS1 recently discovered E3 ubiquitin ligase p300. Hence, observed BRMS1 rescued degradation cisplatin-treated, iASPP-depleted cells. Therefore, hypothesize inhibition constitutes molecular mechanism underlying increased presence iASPP. Furthermore, discovered, malignant melanoma characterized by down-regulated expression level. Follow-up studies low correlated levels some could up-regulate level, suggesting down-regulation leads melanoma, allowing activity Treatment MKP-1 inhibitor BCI, re-establish level induce p300-dependent yet unknown mechanisms. Summing up, regulator function. It enhancing its damage. Re-establishment iASPP-expressing might represent novel strategy overcome chemoresistance.