Figures & data
Table 1 List of published mutant p53 interactions and their functional impact
Figure 1 Mutant p53 (mutp53) interacts with various transcription factors (TFs) to reprogram gene expression in cancer cells.
Notes: (A) Mutp53 forms a complex with NFY, p300, PELP1, and TopBP1 to control expression of genes involved in cell proliferation and in resistance to DNA-damaging drugs.Citation23–Citation25 (B) Mutp53 binds with YAP and NFY on the promoters of genes involved in cell growth and proliferation; both mechanical inputs and activation of the mevalonate pathway control formation and activity of this protein complex.Citation26–Citation28,Citation87 (C) By interacting with SREBP2, mutp53 controls expression of enzymes involved in the mevalonate pathway, promoting cholesterol and fatty-acid biosynthesis, sustaining disruption of mammary-tissue architecture, and inhibiting mechanisms of mutp53 degradation.Citation27–Citation29,Citation87,Citation93 (D) By interacting with NRF2, mutp53 controls expression of multiple subunits of the proteasome, alleviating proteotoxic stress and accelerating turnover of cell-cycle inhibitors.Citation30 (E) In a complex with HSF1, mutp53 controls expression of chaperones and heat-shock proteins that in turn promote mutp53 stability.Citation33 (F) Mutp53 may interact with additional transcription factors, potentially controlling expression of different gene sets, to mediate its oncogenic gain of function.
Figure 2 Mutant p53 (mutp53) forms complexes with cytoplasmic mediators of signal transduction.
Notes: (A) Mutp53 binds and inhibits the tumor suppressor DAB2IP in the cytoplasm of breast cancer cells, reducing TNF-induced activation of the proapoptotic ASK1–JNK axis, simultaneously promoting activation and of proinvasive NFκB transcription factor.Citation62 (B) Mutp53 inhibitory action on DAB2IP promotes insulin-induced activation of the PI3K–Akt pathway, enhancing cell proliferation and invasion in hormone-independent breast and prostate cancers.Citation63 (C) Mutp53 binds the AMPKα subunit and inhibits AMPK activation upon energy stress. This leads to increased anabolic growth of tumor cells and cancer progression.Citation64 (D) Mutp53 binds the monomeric GTPase Rac1, protecting it from SENP1-mediated de-SUMOylation. SUMOylated Rac1 is more active, sustaining tumor growth and dissemination.Citation65
Figure 3 Therapeutic approaches targeting mutant p53 (mutp53) protein complexes.
Notes: Pharmacological approaches aimed at disrupting mutp53 complexes represent an appealing strategy for cancer therapy. Such approaches involve stabilizing mutp53 to restore its wild-type functions, reducing mutp53 levels by disrupting mechanisms of mutp53 accumulation, counteracting mutp53 activity by targeting specific mutp53 modulators, preventing or disrupting oncogenic complexes with specific target proteins, and inhibiting mediators or pathways downstream of mutp53 protein complexes (see text for details).
