We know from our experience, intuition, and scads of studies that the body reacts to stress – often negatively. For the most part, long term stress is harmful. There are many muscular, neurological, vascular, and digestive reactions (to name a few) that if not significantly relieved by some point, turn toward physical degeneration and disease – ulcers, neuroses, arthritis, heart attacks – among many. We are familiar with the causes, we know most of the symptoms, and for the most part we know what organs are involved. What we don’t know all that much about in useful detail are the molecular, cellular, and genetic pathways that are involved in stress reactions. It’s an area where research has been underway for only a decade or three (and sometimes much less). So it’s not surprising that with some regularity discoveries are made that reveal wholly unknown processes.

A good example is the recently published research from a team led by scientists at the University of Pennsylvania School of Medicine (USA) in Science Express [Signaling Kinase AMPK Activates Stress-Promoted Transcription via Histone H2B Phosphorylation]. Their work shows that the master regulator of cell energy production, AMP-activated protein kinase or AMPK, is also responsible for interacting with cell DNA under conditions of stress to increase, slow-down, or even stop cell growth. The energy role of AMPK has been known for decades; the epigenetic role was unknown.

AMPK is a regulator protein present in almost all forms of life, which means its function is basic and very old. When cells run low on energy, it is AMPK that interacts with about eleven genes to increase the production of energy; it also works in reverse to slow down energy production as needed. This function of AMPK is fairly well understood, as it is a crucial signaling protein for numerous energy related chemical pathways in the cell. What was not known is that AMPK can also perform a similar regulatory function for cell growth.

The research that led to this conclusion started with the knowledge that AMPK is one of the main signaling molecules for cellular stress. Running low (or high) on cell energy is one kind of stress. There are others, mostly the presence (or lack) of certain chemicals that also signify cell stress. To test the reaction of cells to stress, the scientists used high levels of ultraviolet radiation and manipulation of the glucose supply (sugar energy) for tissue culture cells (cells growing in a Petri dish). They discovered that the AMPK picks up the stress signal, penetrates the nucleus of the cell where it binds with the p53 protein (a known tumor suppressor). In turn, the p53 protein produces a phosphate (molecular structure) that binds to a histone (a type of protein that surrounds and supports the cell’s DNA) near gene p21 – one of the genes responsible for regulating the cell’s growth cycle.

This interaction between AMPK and the genes of the DNA is known as epigenetics, which is well described here:

Unlike genetic changes, which involve a change or mutation in DNA sequence, epigenetic changes in the nucleus leave the DNA sequence unaltered but modify the histone proteins, which comprise the backbone of the chromosome. Histones are proteins found in the nucleus that package and order DNA into structural units. Epigenetic changes alter how DNA folds in chromosomes, changing how accessible genes are to regulatory proteins and enzymes that copy genes into RNA messages.

[Source: EurekAlert]

In this case, the AMPK molecule acts as the signaling messenger telling the DNA to react to a stress situation by slowing down (or increasing) the rate of cell growth. This makes sense, since if the energy status of the cell is in flux (stressed); it’s not the time for the cell to demand more growth or to begin the process of cell division.

The researchers were surprised by this result because until now it was not known that AMPK itself could be present in the DNA complex (the chromatin), or that it had anything to do with histones or the p53 gene. This connection can now be added to the other gene pathways that AMPK is known to affect.

This finding may have significance for a number of avenues of research, particularly in relation to the drug metformin, which is targeted for AMPK and is commonly used to treat Type II diabetes. This new information about AMPK adds to the impression that the more we know about the spectacularly sophisticated feedback mechanisms built into cellular chemistry (especially with the proteins), the more we will realize that our ‘cures’ and ‘medicines’ have a tendency to upset chemical balances – sometimes leading to negative final results.