Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Cancer suppressor gene links metabolism with cellular aging

14.01.2013
Metabolic control of p53 points to new cancer therapeutics

It is perhaps impossible to overstate the importance of the tumor suppressor gene p53. It is the single most frequently mutated gene in human tumors. p53 keeps pre-cancerous cells in check by causing cells, among other things, to become senescent – aging at the cellular level. Loss 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.

Now, a team of researchers from the Perelman School of Medicine, University of Pennsylvania, has identified a class of p53 target genes and regulatory molecules that represent more promising therapeutic candidates.

As Xiaolu Yang, PhD, professor of Cancer Biology and investigator in Penn's Abramson Family Cancer Research Institute, and his team describe in an advance online Nature publication, 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, Yang says, suggest that p53 acts as a molecular sensor of metabolic stress and explains how metabolic stress can lead to senescence in cells.

"We uncovered an important regulatory mechanism for p53 as well as an effector mechanism for p53," Yang says.

Significantly, the findings also identify malic enzymes as novel and potentially useful pharmaceutical targets for anticancer therapy, as well as possible mediators of the normal aging process – though neither possibility was actually addressed in the current study.

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.

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. Those enzymes could potentially serve as anticancer drug targets, he says. But equally important, they may also play a role in the normal process of cellular aging.

"Senescence is aging at the cellular level," says Yang, who notes that considerable research has demonstrated a correlation between caloric restriction and lifespan. "We may have identified a good starting point to understand how aging works."

Other co-authors include Peng Jiang, Wenjing Du, Anthony Mancuso, and Kathryn Wellen, all from Penn.

The study was funded by the National Cancer Institute (CA088868) and the Department of Defense (W81XWH-10-1-0468).

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine is currently ranked #2 in U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $479.3 million awarded in the 2011 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation's first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2011, Penn Medicine provided $854 million to benefit our community.

Karen Kreeger | EurekAlert!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht Programming cells with computer-like logic
27.07.2017 | Wyss Institute for Biologically Inspired Engineering at Harvard

nachricht Identified the component that allows a lethal bacteria to spread resistance to antibiotics
27.07.2017 | Institute for Research in Biomedicine (IRB Barcelona)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Physicists Design Ultrafocused Pulses

Physicists working with researcher Oriol Romero-Isart devised a new simple scheme to theoretically generate arbitrarily short and focused electromagnetic fields. This new tool could be used for precise sensing and in microscopy.

Microwaves, heat radiation, light and X-radiation are examples for electromagnetic waves. Many applications require to focus the electromagnetic fields to...

Im Focus: Carbon Nanotubes Turn Electrical Current into Light-emitting Quasi-particles

Strong light-matter coupling in these semiconducting tubes may hold the key to electrically pumped lasers

Light-matter quasi-particles can be generated electrically in semiconducting carbon nanotubes. Material scientists and physicists from Heidelberg University...

Im Focus: Flexible proximity sensor creates smart surfaces

Fraunhofer IPA has developed a proximity sensor made from silicone and carbon nanotubes (CNT) which detects objects and determines their position. The materials and printing process used mean that the sensor is extremely flexible, economical and can be used for large surfaces. Industry and research partners can use and further develop this innovation straight away.

At first glance, the proximity sensor appears to be nothing special: a thin, elastic layer of silicone onto which black square surfaces are printed, but these...

Im Focus: 3-D scanning with water

3-D shape acquisition using water displacement as the shape sensor for the reconstruction of complex objects

A global team of computer scientists and engineers have developed an innovative technique that more completely reconstructs challenging 3D objects. An ancient...

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

 
Latest News

Programming cells with computer-like logic

27.07.2017 | Life Sciences

Identified the component that allows a lethal bacteria to spread resistance to antibiotics

27.07.2017 | Life Sciences

Malaria Already Endemic in the Mediterranean by the Roman Period

27.07.2017 | Health and Medicine

VideoLinks
B2B-VideoLinks
More VideoLinks >>>