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.

Mutant p53 interactome identifies nardilysin as a p53R273H‐specific binding partner that promotes invasion

“…The p53R273H protein mediates invasion towards EGF through its ability to inactivate p63, while, as shown here, invasion to HB-EGF can be mediated through a new and highly specific biochemical interaction with NRD1. Our observations that mutant p53 can cooperate with NRD1 to promote invasion are consistent with several recent studies [10][11][12]14,[16][17][18]32] that demonstrated a neomorphic ability of mutant p53 to promote invasion. One mechanism underlying this gain of function of mutant p53 is an inhibition of the p53 family member p63, thereby promoting invasion responses to two important growth factors; EGF [11] and tumour growth factor-b [10].…”

“…Mechanisms underlying the oncogenic nature of mutant p53 include interaction or regulation of other transcription factors including p63, p73, NF-Y and VDR [12][13][14][15] or additional binding proteins such as TOPBP1, ANKRD11 and PIN1 [16][17][18]. Nearly all of the large number of interacting proteins reported in IARC p53 database [2] bind to wt-p53 and are therefore not good candidates for the neomorphic mutant hypothesis.…”

Mutant p53 drives invasion in breast tumors through up-regulation of miR-155

“…ZR-75-1 and BT549 cells were maintained in RPMI supplemented with 10% FBS and 1mM sodium pyruvate. H1299 cells with inducible expression of wild-type or mutant p53 are as described previously (35). H1299 and ZR-75-1 were engineered to express either miR-155 or a non-targeting SCR control through retroviral mediated transduction with viruses generated by the pMSCV-Puro-GFP-miR-155 or pGIPZ-nontargeting (Open Biosystems) vectors, followed by selection in 500ng/mL puromycin (Sigma Aldrich, Castle Hill, NSW).…”

Mutant p53 gain of function can be at the root of dedifferentiation of human osteosarcoma MG63 cells into 3AB-OS cancer stem cells

“…It is known that TP53 mutations occur in almost every type of cancer and often mutant p53 proteins (mutp53) express gain of function (GOF), which can enhance the ability of cancer cells to invade and metastasize, confer resistance to chemotherapies, promote genomic instability and drive multinucleation [18][19][20][21][22][23][24][25][26][27]. Recently, evidence linking p53 loss to stem-like phenotype in cancer has been reported [28]; however, how p53 contributes to acquisition of "stemness" at the molecular level and whether stem-like cells confer survival advantages to propagate the tumor remains to be resolved.…”