Invited Speaker 35th Lorne Cancer Conference 2023

Oncogenic activities of mutant p53 and Mdm2 (#2)

Carol Prives 1
  1. Columbia University, New York, United States

The p53 tumor suppressor, a tetrameric DNA sequence-dependent transcriptional activator, is mutated with high frequency in many forms of cancer. Li Fraumeni Syndrome (LFS) patients harbor germ-line mutations in p53 and are extremely prone to certain forms of cancer. Two well studied negative regulators of wild-type p53, Mdm2 and its homologue MdmX, are known to have p53-independent functions.  Two recent studies on mutant p53 and Mdm2/X will be presented.

A mutant p53 (A347D) found in a subset of LFS patients can form dimers but not tetramers. We used cells derived from LFS patients harboring the p53(A347D) mutation as well as CRISPR-engineered U2OS cancer cells to study the impact of this mutation. We found that A347D confers tumorigenic properties to cells that are similar to those that do not express any p53.  Yet, in contrast to cells with wild-type p53 or no p53, cells with p53(A347D) display an altered mitochondrial morphology, a glycolytic phenotype and heightened sensitivity to select chemotherapeutics. Interaction of the mutant p53 protein with mitochondria elicits apoptotic cell death upon treatment with such chemotherapeutic agents and this occurs in the absence of transcription.   Thus, dimer-forming mutant p53(A347D) displays both loss of wild-type p53 functions as well as unique neomorphic gain-of-function activities.

We discovered that in select cell lines that lack wild-type p53, knockdown of Mdm2, MdmX or pharmacological inhibition of Mdm2/X E3 ligase activity reduces cell migration in 2D cultures and invasion from preformed spheroids into collagen-based matrices. Loss or inhibition of Mdm2/X also impairs cell spreading, attachment to extracellular matrix (ECM) components, and formation of focal adhesions. Further, our results show that in cells lacking p53, Mdm2 can promote metastasis. Remarkably, we found that Mdm2 modulation of Sprouty4 is needed for Mdm2 to promote metastasis-related activities in these cell lines. The implications of these findings will be discussed.