worm and cancer connection?

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A gene that controls rhythmic events in worm's life discovered

 

Researchers at the University of Utah found a gene that controls

rhythmic events in a worm's life: swallowing food, laying eggs and

pooping.

 

If the gene is disabled, the worms can't swallow, so they die. If the

gene is partly restored so the worms can swallow, they have trouble

reproducing and get constipated.

 

" We have found a gene that is important for the control of

fundamental rhythms in nematode worms, " says Andres Villu Maricq, a

member of the Brain Institute at the University of Utah. " The same

gene products that control the fundamental processes of life in

mammals also are found in the worm, so our study suggests this gene

and related genes may have critical roles in controlling rhythmic

behaviors in humans and other animals. "

 

Discovery of the gene is reported in the journal Cell.

 

The study deals with seconds- to hours-long ultradian rhythms that

control such body functions as heart rate, breathing, swallowing and

contraction of the intestines.

Much less is known about ultradian rhythms than about circadian

rhythms, which regulate the 24-hour cycle of sleeping, waking and

activity, Maricq says.

 

The gene that controls ultradian rhythms in worms is related to other

genes that, when mutated, cause uncontrolled growth of mammalian cells

– a hallmark of cancer. By learning how the gene works, researchers

may learn how to interfere with it – a possible way to find new cancer

drugs

 

Maricq and colleagues studied Caenorhabditis elegans, a

millimeter-long ( one 25th of an inch ) nematode worm that is found in

soil, eats bacteria and frequently is used by geneticists. The

researchers discovered a worm gene they named vav-1 – which is related

to three similar human genes. The study showed that the gene

controlled the rhythmic contractions of smooth muscle in three parts

of the worm's body by regularly raising and lowering calcium levels in

the muscle cells:

 

- The pharynx, which is the worm equivalent of the throat and must

undergo a wave-like expansion and contraction every one or two seconds

so the worm can swallow.

 

- The gonadal sheath, a tube-like smooth muscle structure that

contracts every seven seconds during ovulation, squeezing out eggs so

they can be fertilized by sperm.

 

- The intestines, which must pressurize and then release so the worm

can defecate every 45 to 50 seconds.

 

When the scientists disabled the vav-1 gene, the worms could not

swallow food and died before the end of the first of four larval

stages, or 10 to 12 hours into their normal two-week lifespan.

 

When the researchers restored the vav-1 gene just in the pharynx so

worm larvae could eat, survive and grow to adulthood, the worms rarely

were able to produce offspring and their 50-second defecation cycle

became irregular, with the mean time between poops increasing to 195

seconds, or 3¼ minutes.

 

" The worm can swallow and live and grow up to be an adult with really

bad constipation, " Maricq says. " Mutants sometimes have to wait six

to 10 minutes. "

 

The Brain Institute " is interested in the molecular control of

behavior – how our nervous system works, " Maricq says. " Vav is found

in the brain, and we now show this gene, vav-1, is of central

importance for the control of rhythmic behaviors. "

 

Researchers do not know if vav genes control human swallowing,

ovulating or defecating, " but it will be an obvious avenue for further

research, " he adds. " Almost all of our behaviors are rhythmic:

breathing, swallowing, heartbeats and brain activity. "

 

The cancer connection

 

The worm vav-1 gene is analogous to known " proto-oncogenes " in

mammals – genes that are used by the body for various normal

processes, but, when mutated, may become an oncogene, or

cancer-causing gene.

 

Mutant vav genes have been shown to cause cancer-like changes in

cells, but it has not yet been shown they cause cancer in humans, who

have three vav genes.

 

" We don't know that much about what they do, " except that when immune

cells are stimulated by bacteria or other invaders, vav genes help

increase the cells' calcium levels, which sends a wake-up signal to

the rest of the immune system, Maricq says.

 

Other genes and their proteins turn vav-1 on and off. When such

control is eliminated, vav-1 is unleashed, so cells grow out of

control and may become cancerous.

 

Thus, vav-1 is one of the " players in the cascade of events that may

lead to cancer, " Maricq says. " The reason you want to know the

players is that each one represents a potential target for drugs, a

potential way to stop the process. "

 

Worms with cancer-causing vav-1 might be used to test possible new

anti-cancer drugs. If the oncogene causes a change in the worm's

rhythmic behavior, then drugs that stop the behavior change also might

work against cancer, Maricq says.

 

Finding the rhythm gene

 

Maricq's team discovered the vav-1 gene in worms by starting with the

mammal version of the gene, then looking in the worm's genetic

blueprint, for similar genes.

 

Next, the researchers determined where vav-1 worked by tagging it with

green fluorescent protein. The pharynx, gonadal sheath and intestines

glowed green.

 

To test what the vav-1 gene did, the researchers bred worms that

lacked the gene. " They were born, but died soon thereafter because

they couldn't eat, " Maricq says.

 

The worms were not missing the mouth or other body parts, " but there

was no pumping of the pharynx, " he adds. As a test, the biologists

inserted the gene back into the pharynx, but not the rest of the worm.

As a result, the worms could eat and develop to adulthood, but then

developed defects in ovulating and pooping.

 

C. elegans worms are hermaphrodites – both male and female – and make

their own sperm and eggs. Rhythmic contractions control how the eggs

are pushed down the tube-like gonadal sheath and into the spermatheca,

which contains sperm.

 

When vav-1 is disabled, the worms " have almost no progeny, " Maricq

says. " They don't have the proper synchronized ovulation. The egg has

to be timed to enter the spermatheca at the right time because the

spermatheca is contracting. It can cut eggs up when timing is off. "

And without proper rhythmic contractions, eggs also may be too young

or too old to be fertilized when they reach the spermatheca.

 

As part of the study, the researchers shut down various genes to

demonstrate the chain of molecular events in which vav-1 acts like a

switch to control calcium levels in cells and thus the contractions

responsible for swallowing, ovulating and defecating.

 

The chain begins when the vav-1 gene is used to make the protein

VAV-1. The protein activates other proteins made by what are known as

Rho/Rac genes. Then the Rho/Rac proteins turn other genes and proteins

on and off.

 

The study found that when Rho/Rac proteins are turned on, levels of a

chemical named IP3 increase in cells. IP3 attaches to " receptors " on

the endoplasmic reticulum, a calcium-filled membrane bag inside each

cell. IP3 makes the endoplasmic reticulum release calcium into the

cell. Ups and downs in calcium levels control the rhythmic

contractions responsible for swallowing, ovulating and pooping in worms.

 

Source: University of Utah, 2005

 

 

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