Of Hedgehogs and Cancer

Indian scientists have discovered that a protein essential for growth turns hostile and causes cancer.

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Indian researchers in Bangalore have solved a puzzle that has been haunting scientists for a long time: how does a set of proteins that are crucial for the well-rounded development of organisms trigger cancers?

The work, spearheaded by scientists at the National Centre for Biological Sciences (NCBS), provides a significant insight into the erratic behaviour of Hedgehog proteins, named so because their absence gives embryos a prickly appearance.

The Hedgehog protein is aptly described as the construction supervisor of life, as it plays a critical role in directing an organism’s growth from a single fertilised egg to a collection of millions of structured, specialised cells. They ensure, among other things, that the hands and feet develop the right shape and number of digits, the heart is located on the left and not the right side of the body, and that we have two eyes and ears instead of one each.

For more than a decade, scientists have been trying to understand the protein’s role in deciding which group of cells should constitute a particular tissue or organ (such as nerves, muscles and liver). In the process they found that when the Hedgehog genes of lab animals were knocked off or mutated, the progenies were born without wings or limbs or eyes, clearly indicating their pivotal role in the overall growth of organisms.

But once an organism, including humans, grows into an able-bodied creature, the Hedgehog proteins are left with a minimal role to play, quite like a supervisor’s role that comes to an end once the building is up and occupied. Except that both need to be available for occasional repair jobs.

Earlier in the decade, a team of researchers led by Philip Beachy of the Johns Hopkins School of Medicine discovered that the protein is not entirely harmless: it causes medulloblastoma, one of the most common brain cancers in children. Since then researchers elsewhere have found the Hedgehog’s involvement in cancers of several other organs — small cell lung cancer, pancreatic and prostrate cancers and so on.

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Over the years, it has become clear to scientists that in order to be “mischievous,” the Hedgehog proteins need to be hyperactive so that they are able to work on cells that are far away from their location. “How the Hedgehog proteins are able to ‘jump’ to cells far away from their parent cells remained a mystery for long,” says Neha Vyas, the first author of the paper that appeared in the prestigious journal Cell in the last week of June.

Vyas, a post doctoral student at Satyajit Mayor’s lab at NCBS, says they got interested in Hedgehog proteins for an entirely different reason. It is one of the few proteins in the body that requires cholesterol — a fatty substance often vilified for clogging arteries — for efficient functioning. Studies have shown that inadequate cholesterol levels in an expectant mother can mar the development of the baby in many ways. “Hence we were interested in the protein’s cholesterol link,” she says.

“It became clear to us that for the Hedgehog molecules to be able to act over a distance, two kinds of interactions are needed. The molecules need to come together and also collaborate with a group of special carriers which are required to ferry them across a long distance,”NCBS director K. VijayRaghavan, a co-author of the study, told KnowHow.

Clustering is a normal activity of the Hedgehog protein. But it leads to cancer when the Hedgehog is made when it should not be or cells act as if they are constantly “seeing” these proteins even when they are not, observes VijayRaghavan.

The scientists — including those from the University of Mysore and the Centre for Cellular and Molecular Biology in Hyderabad — found that Hedgehog proteins exploit the electrostatic interactions of amino acids on their surface for clustering, the first step in the long journey away from the parent cell. The scientists understood the mechanism by which Hedgehog proteins “move around” and also that deactivating a single amino acid on the protein’s surface puts an end to the formation of clusters and hence its unattended long haul.

“Identifying this initial step is of great help as it could be used to design an anti-cancer drug that could stall a mutant Hedgehog pathway,” says Vyas. “Drug designers could target it at the very source itself.”

However, developing a drug that can safely defuse the hyper Hedgehogs that cause the biological mayhem called cancer is not all that easy. Blocking the Hedgehog protein has to be very selective as it plays a role in the regeneration of organs and tissues.

“It is not clear how much regeneration in adults is dependent on Hedgehog proteins, but recent stem cell studies have shown that they are important,” says Mayor, the lead author. A cancer cell-targeted inhibitor should be the way to go, he sums up.

Sources: The Telegraph (kolkata, India)

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