title: Mutant p53 drives multinucleation and invasion through a process that is suppressed by ANKRD11.
abstract: Mutations of p53 in cancer can result in a gain of function associated with tumour progression and metastasis. We show that inducible expression of several p53 'hotspot' mutants promote a range of centrosome abnormalities, including centrosome amplification, increased centrosome size and loss of cohesion, which lead to mitotic defects and multinucleation. These mutant p53-expressing cells also show a change in morphology and enhanced invasive capabilities. Consequently, we sought for a means to specifically target the function of mutant p53 in cancer cells. This study has identified ANKRD11 as a key regulator of the oncogenic potential of mutant p53. Loss of ANKRD11 expression with p53 mutation defines breast cancer patients with poor prognosis. ANKRD11 alleviates the mitotic defects driven by mutant p53 and suppresses mutant p53-mediated mesenchymal-like transformation and invasion. Mechanistically, we show that ANKRD11 restores a native conformation to the mutant p53 protein and causes dissociation of the mutant p53-p63 complex. This represents the first evidence of an endogenous protein with the capacity to suppress the oncogenic properties of mutant p53.
authors: Cancer Therapeutics Laboratory, Discipline of Medicine, University of Adelaide, Adelaide, South Australia, Australia. jacqueline.noll@adelaide.edu.au
authors: J E
authors: JE
authors: Noll
authors: J
authors: J
authors: Jeffery
authors: F
authors: F
authors: Al-Ejeh
authors: R
authors: R
authors: Kumar
authors: K K
authors: KK
authors: Khanna
authors: D F
authors: DF
authors: Callen
authors: P M
authors: PM
authors: Neilsen
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D048750:Cell Nucleus Division / Q000235:genetics*; D018385:Centrosome / Q000502:physiology; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047468:Immunoprecipitation; D009154:Mutation / Q000235:genetics*; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism
chemical_list: C492515:ANKRD11 protein, human; D012333:RNA, Messenger; D012097:Repressor Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53