title: DNAJA1 controls the fate of misfolded mutant p53 through the mevalonate pathway.
abstract: Stabilization of mutant p53 (mutp53) in tumours greatly contributes to malignant progression. However, little is known about the underlying mechanisms and therapeutic approaches to destabilize mutp53. Here, through high-throughput screening we identify statins, cholesterol-lowering drugs, as degradation inducers for conformational or misfolded p53 mutants with minimal effects on wild-type p53 (wtp53) and DNA contact mutants. Statins preferentially suppress mutp53-expressing cancer cell growth. Specific reduction of mevalonate-5-phosphate by statins or mevalonate kinase knockdown induces CHIP ubiquitin ligase-mediated nuclear export, ubiquitylation, and degradation of mutp53 by impairing interaction of mutp53 with DNAJA1, a Hsp40 family member. Knockdown of DNAJA1 also induces CHIP-mediated mutp53 degradation, while its overexpression antagonizes statin-induced mutp53 degradation. Our study reveals that DNAJA1 controls the fate of misfolded mutp53, provides insights into potential strategies to deplete mutp53 through the mevalonate pathway-DNAJA1 axis, and highlights the significance of p53 status in impacting statins' efficacy on cancer therapy.
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors: Alejandro
authors: A
authors: Parrales
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors: Atul
authors: A
authors: Ranjan
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors: Swathi V
authors: SV
authors: Iyer
authors: Department of Chemistry, Abeda Inamdar Senior College, Pune, Maharashtra 411001, India.
authors: Subhash
authors: S
authors: Padhye
authors: Department of Pharmacology, Toxicology and Therapeutics, Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors: Scott J
authors: SJ
authors: Weir
authors: High Throughput Screening Laboratory, University of Kansas, Lawrence, Kansas 66047, USA.
authors: Anuradha
authors: A
authors: Roy
authors: Department of Cancer Biology, University of Kansas Medical Center, Kansas City, Kansas 66160, USA.
authors: Tomoo
authors: T
authors: Iwakuma
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000378:metabolism; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008798:Mevalonic Acid / Q000494:pharmacology; D009154:Mutation / Q000235:genetics*; D011485:Protein Binding / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C107481:DNAJA1 protein, human; D050956:HSP40 Heat-Shock Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D004247:DNA; D008798:Mevalonic Acid