Gain of function properties of mutant p53 proteins at the mitotic spindle cell cycle checkpoint

Mutations in the p53 tumor suppressor gene locus predispose human cells to chromosomal instability. This is due in part to interference of mutant p53 proteins with the activity of the mitotic spindle and postmitotic cell cycl e checkpoints. Recent data demonstrates that wild type p53 is required for postmitotic checkpoint activity, but plays no role at the mitotic spindle c heckpoint. Likewise, structural dominant p53 mutants demonstrate gain-of-fu nction properties at the mitotic spindle checkpoint and dominant negative p roperties at the postmitotic checkpoint. At mitosis, mutant p53 proteins in terfere with the control of the metaphase-to-anaphase progression by up-reg ulating the expression of CKs1, a protein that mediates activatory phosphor ylation of the anaphase promoting complex (APC) by Cdc2. Cells that carry m utant p53 proteins overexpress CKs1 and are unable to sustain APC inactivat ion and mitotic arrest. Thus, mutant p53 gain-of-function at mitosis consti tutes a key component to the origin of chromosomal instability in mutant p5 3 cells.