title: Restoring p53 function in human melanoma cells by inhibiting MDM2 and cyclin B1/CDK1-phosphorylated nuclear iASPP.
abstract: Nearly 90% of human melanomas contain inactivated wild-type p53, the underlying mechanisms for which are not fully understood. Here, we identify that cyclin B1/CDK1-phosphorylates iASPP, which leads to the inhibition of iASPP dimerization, promotion of iASPP monomer nuclear entry, and exposure of its p53 binding sites, leading to increased p53 inhibition. Nuclear iASPP is enriched in melanoma metastasis and associates with poor patient survival. Most wild-type p53-expressing melanoma cell lines coexpress high levels of phosphorylated nuclear iASPP, MDM2, and cyclin B1. Inhibition of MDM2 and iASPP phosphorylation with small molecules induced p53-dependent apoptosis and growth suppression. Concurrent p53 reactivation and BRAFV600E inhibition achieved additive suppression in vivo, presenting an alternative for melanoma therapy.
authors.affiliation: Ludwig Institute for Cancer Research, University of Oxford, Oxford OX3 7DQ, UK.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.forename: Hilde
authors.initials: H
authors.lastname: Breyssens
authors.forename: Victoria
authors.initials: V
authors.lastname: Salter
authors.forename: Shan
authors.initials: S
authors.lastname: Zhong
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.forename: Caroline
authors.initials: C
authors.lastname: Baer
authors.forename: Indrika
authors.initials: I
authors.lastname: Ratnayaka
authors.forename: Alex
authors.initials: A
authors.lastname: Sullivan
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Brown
authors.forename: Jane
authors.initials: J
authors.lastname: Endicott
authors.forename: Stefan
authors.initials: S
authors.lastname: Knapp
authors.forename: Benedikt M
authors.initials: BM
authors.lastname: Kessler
authors.forename: Mark R
authors.initials: MR
authors.lastname: Middleton
authors.forename: Christian
authors.initials: C
authors.lastname: Siebold
authors.forename: E Yvonne
authors.initials: EY
authors.lastname: Jones
authors.forename: Elena V
authors.initials: EV
authors.lastname: Sviderskaya
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
authors.forename: Thomas
authors.initials: T
authors.lastname: John
authors.forename: Otavia L
authors.initials: OL
authors.lastname: Caballero
authors.forename: Colin R
authors.initials: CR
authors.lastname: Goding
authors.forename: Xin
authors.initials: X
authors.lastname: Lu
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D056744:Cyclin B1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019281:Dimerization; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis / Q000378:metabolism*; D059566:M Phase Cell Cycle Checkpoints; D008545:Melanoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis; D015739:Nocodazole / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis / Q000378:metabolism; D012097:Repressor Proteins / Q000032:analysis / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C534699:CCNB1 protein, human; D056744:Cyclin B1; D007093:Imidazoles; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; C506121:JNJ-7706621; C119612:PPP1R13L protein, human; D010879:Piperazines; D012097:Repressor Proteins; D013449:Sulfonamides; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; D000077484:Vemurafenib; C482205:nutlin 3; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D016203:CDC2 Protein Kinase; D015739:Nocodazole