Regulation of Cell Senescence Depends on Malic Enzymes Interacting with the p53 Tumor Suppressor

The role of the p53 tumor suppressor gene in regulating cell senescence may involve interacting in a positive feedback mechanism with the tricarboxylic-acid-cycle-associated malic enzymes ME1 and ME2.

The tumor suppressor protein p53 is normally found at low levels, but when DNA damage is sensed, p53 levels rise and initiate protective measures. The protein binds to many regulatory sites in the genome and begins production of proteins that halt cell division until the damage is repaired. Or, if the damage is too severe, p53 initiates the process of apoptosis, permanently removing the damage. Mutations in the p53 gene contribute to about half of the cases of human cancer. Most of these are missense mutations, changing the information in the DNA at one position and, by inserting an incorrect amino acid at one point in the protein chain, causing the cell to produce p53 with an error. In these mutants, normal p53 function is blocked and the protein is unable to stop multiplication of the damaged cell. If the cell has other mutations that cause uncontrolled growth, it will develop into a tumor.

A paper published in the January 13, 2013, online edition of the journal Nature on the relationship between p53 and cell senescence linked the activity of the tumor suppressor to a specific metabolic process. Investigators at the University of Pennsylvania (Philadelphia, USA) found that in both cell cultures and a mouse model p53 was critically involved in the functioning of the malic enzymes ME1 and ME2. Both malic enzymes are important for NADPH production, lipogenesis, and glutamine metabolism, but ME2 has a more profound effect.

Results indicated that through the inhibition of the malic enzymes, p53 regulated cell metabolism and proliferation. Downregulation of ME1 and ME2 reciprocally activated p53 through a distinct mechanism in a feed-forward manner, bolstering this pathway and enhancing p53 activation. Downregulation of ME1 and ME2 also modulated the outcome of p53 activation, leading to strong induction of senescence, but not apoptosis, whereas enforced expression of either malic enzyme suppressed senescence.

In the mouse model, loss of either ME1 or ME2 reduced tumor weight, even in animals genetically engineered to lack the p53 gene. In contrast, overexpression of malic enzymes led to more substantial tumors.

"Those enzymes could potentially serve as anticancer drug targets," said senior author Dr. Xiaolu Yang, professor of cancer biology at the University of Pennsylvania." But, equally important, they may also play a role in the normal process of cellular aging. Senescence is aging at the cellular level. We may have identified a good starting point to understand how aging works."

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