A team of researchers from the University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates.
The tumor suppressor gene p53 is the single most frequently mutated gene in human tumors, as it keeps pre-cancerous cells in check by causing cells, among other things, to become senescent - aging at the cellular level.
AdvertisementLoss of p53 causes cells to ignore the cellular signals that would normally make mutant or damaged cells die or stop growing.
In short, the p53 pathway is an obvious and attractive target for drug developers.
But that strategy has so far proven difficult, as most p53 regulatory proteins operate via protein-protein interactions, which make for poor drug targets, as opposed to ones based on enzymes.
As Xiaolu Yang, PhD, professor of Cancer Biology and investigator in Penn's Abramson Family Cancer Research Institute, and his team describe, p53 participates in a molecular feedback circuit with malic enzymes, thereby showing that p53 activity is also involved in regulating metabolism.(The Yang lab identified p53's role in glucose metabolism in the past.)
The new findings suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells, Yang said.
"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang said.
As cells become damaged and precancerous, the p53 protein prevents those cells from continuing towards becoming tumors by causing the cells to senesce.
Metabolic cues also regulate senescence, but the molecular relays coupling those two processes-senescence and metabolism-remained unknown.
The study is published in the online journal Nature.