Academic Communication

Academic Report:Surprising roles of p53 and Mdm2 in regulating metabolism of cancer cells2019-05-09

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  Subject: Surprising roles of p53 and Mdm2 in regulating metabolism of cancer cells

  Speaker: Professor Carol Prives

  Time:      14:00 on May 13th, 2019

  Location:Room 201 in First Teaching Biulding

  Abstract:

  Despite decades of intense scrutiny we still do not fully understand how p53 functions as a tumor suppressor in its wild-type state, and as an oncogene when harboring cancer-related mutations. Further, we have yet to clarify the roles of Mdm2 and MdmX, most well understood as negative regulators of p53, in p53-independent activities. Work from our lab has revealed that p53 and Mdm2 can regulate metabolism in different ways. For example, in collaboration we discovered that while mutant p53 upregulates the mevalonate pathway by which cells synthesize cholesterol and key byproducts that play roles in cell growth, in complete opposition to this wild-type p53 can repress expression of the genes encoding the mevalonate pathway enzymes. In collaboration with the group of Scott Lowe it was shown that that p53 repression of the mevalonate pathway is required for prevention of hepatocellular carcinoma in mice.

  In separate studies, we found that Mdm2 and MdmX play one or more roles in maintaining growth and survival of some cancer cell lines. Interestingly, however, I collaboration with Brent Stockwell, we discovered that the same cells when induced to undergo  ferroptosis, which is an iron-dependent form of cell death caused by lipid peroxidation, actually require Mdm2 and MdmX for maximal response to inducers of ferroptosis. Insight into how Mdm2 and MdmX play such roles will be presented.

  Finally, our studies of mutant p53 that can form dimers but not tetramers has revealed an novel role for p53 in regulating glycolysis. Oligomerization-defective mutant forms of p53 display a distinct phenotype marked by enhanced glucose influx and antioxidant generation. Despite elevated antioxidant pools, dimeric mutant cells display increased basal ROS and significantly morphologically aberrant mitochondria characteristic of stressed cells. Consistent with this finding, these mutant cells are highly vulnerable to DNA damage response inducers.

  Taken together our findings reveal unanticipated roles of p53 in regulating lipid and glycolytic metabolism.