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HMGB1 represses the anti-cancer activity of sunitinib by governing TP53 autophagic degradation via its nucleus-to-cytoplasm transport.

Autophagy. 2018; 
Luo P, Xu Z, Li G, Yan H, Zhu Y, Zhu H, Ma S, Yang B, He Q.
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Catalog Antibody 5, 150 mM NaCl, 1 mM EDTA, 1% NP-40 (Beyotime, ST366) with protease inhibitor cocktail (Cell Signaling Technology, 5871) and were used for an overnight immunoprecipitation (500 μg per sample) at 4°C with 10 μL of the following antibodies: anti-FLAG (GenScript, L00425); anti-TP53 (Santa Cruz Biotechnology, sc-47698); anti-HMGB1 (Santa Cruz Biotechnology, sc-26351) and anti-SQSTM1 (Santa Cruz Biotechnology, sc-48402). Get A Quote

摘要

Sunitinib, a multikinase inhibitor approved for a number of cancer indications has a low response rate. Identifying mechanisms of resistance could lead to rational combination regimens that could improve clinical outcomes. Here we report that resistance to sunitinib therapy was driven by autophagic degradation of TP53/p53. Deletion of ATG7 or ATG5 suppressed TP53 degradation, as did knockdown of SQSTM1/p62. Mechanistically, the transport of TP53 from the nucleus to the cytoplasm was essential for the sunitinib-induced autophagic degradation of TP53 and did not require TP53 nuclear export signals (NESs). Moreover, TP53 degradation was achieved by the transport of its nuclear binding target, HMGB1, which shifted ... More

关键词

Autophagy-lysosomal degradation; HMGB1; TP53; nuclear export; sunitinib