Yang and his team decided to test if a pair of enzymes, malic enzyme 1 and malic enzyme 2 (ME1 and ME2), could be involved. Malic enzymes recycle malate an intermediate molecule back into an end-product of glycolysis pyruvate storing energy in the process. Malic enzymes are important for adjusting metabolic flux to suit proliferating cells' demands for energy and biosynthesis. Thus, these two enzymes are attuned to the energy and proliferative state of the cell.
Yang's team found that p53 inhibits malic enzyme expression, such that loss of p53 causes malic enzyme abundance to increase. Conversely, malic enzymes keep p53 in check; loss of malic enzymes ramps up p53 activation and induces senescence via either downregulation of a p53 inhibitor (Mdm2) or production of oxygen radicals. Overexpression of malic enzymes inhibits senescence.
The result, Yang explains, is a "feed-forward loop" in which activation of p53 suppresses malic enzyme expression, reducing malic enzyme levels and further upregulating p53, leading to senescence. On the other hand, upregulation of malic enzymes inhibits p53. p53 inhibition loosens the protein's grip on malic enzyme expression, allowing malic enzyme levels to rise.
"This is a circuit," he says. "Going around this loop, you get pretty robust activation."
These same results played out in animal models described in the Nature study. Loss of either ME1 or ME2 reduced tumor weight, even with p53-null tumor cells, which suggests an additional, p53-independent function of malic enzymes.And, overexpression of malic enzymes led to more substantial tumors.
According to Yang, the study pegs malic enzymes as molecular players linking senescence and metabolic state.
|Contact: Karen Kreeger|
University of Pennsylvania School of Medicine