Protein interaction causes brain tumors

By: Neil Neumann

Posted: 3/13/08

Researchers from the Sidney Kimmel Comprehensive Cancer Center at the Hopkins medical school have uncovered a detailed interaction between two proteins involved in medulloblastoma, a common type of brain cancer.

This group of researchers has characterized and shown that two proteins involved in the repression of tumor formation work together to switch-off a third protein, which can lead to medulloblastoma formation.

Medulloblastoma is the most common nervous system cancer in children and is thought to arise from granule cell precursors (GCPs) in the cerebellum. The cerebellum, which means "little brain," aids in the integration between sensory inputs and motor control outputs.

It is mainly composed of granule cells, which are tiny in comparison to other neurons of the brain. This characteristic of the granule cells allows the cerebellum take up only 10 percent of the brain's size, but roughly 50 percent of the brain's neurons.

The Hedgehog pathway is involved in many developmental processes, in the cerebellum as well as in other parts of the body. During development, cells in the brain secrete Sonic Hedgehog, a protein that activates the Hedgehog pathway.

This pathway is used extensively in the formation of granule cells from granule precursor cells.

PATCHED-1 (Ptch1) is a receptor on the cell-surface of GCPs that binds to the Sonic Hedgehog protein, thereby activating the Hedgehog pathway within a cell. However, when not activated by this ligand, Ptch1 is also a tumor suppressor protein.

In its presence, it stops the formation of tumors, and in its absence, tumors can form. Interestingly, fewer than 25 percent of medulloblastoma cancers have mutations in the Hedgehog pathway.

The researchers from the medical school wanted to determine what other proteins are involved in the formation of medulloblastoma. Previous work done in the field has shown that mutations, or alterations, to the genome at a certain point show a higher incidence of medulloblastoma formation.

This region contains the other tumor suppressor, known as Hypermethyated In Cancer 1, or Hic1, on which the Hopkins team decided to focus its attention.

Hic1 is also a tumor suppressor. It has been shown that in medulloblastoma cancer cells, there is methylation of the gene, which encodes Hic1.

Methylation is a way for cells to silence genes that it does not want to express proteins. The problem with this is that cells can exploit this mechanism and use it to become cancerous. Since the gene for Hic1 is methylated, the Hic1 protein is not expressed and cannot properly suppress the cell from becoming cancerous.

When the researchers combined mutations of the Ptch protein and the Hic1 protein in a mouse, there was a higher level of medulloblastoma formation. From here, they wanted to know if there was an interaction in the pathway between Ptch, which can repress the Hedgehog pathway, and the Hic1 protein.

Using gene expression and other techniques, the researchers located a target of Hic1, a protein known as Atoh1. When Hic1 interacts with Atoh1, the Atoh1 protein is inactivated and cannot help to form medulloblastoma. However, it has been shown that in medulloblastoma, Atoh1 is highly expressed, implicating its role in tumorigenesis.

Using molecular biology techniques, the researchers were also able to show that Hic1 acts downstream, meaning it acts after other proteins in that pathway, in the Hedgehog pathway, showing a connection between Ptch1, which represses the Hedgehog pathway, and Hic1, which acts downstream in the Hedgehog pathway to stop the activation of Atoh1.

From all of this data the researchers were able to demonstrate that epigenetic regulation of the gene which encodes Hic1 regulates the formation of medulloblastoma.

Epigenetics is the branch of genetics in which the genes stay the same, but modifications can occur on those genes which regulate how they are used.

Thus, in normal granule precursor cells, the Hic1 gene is not methylated and the Hic1 protein can then work properly to suppress the formation of cancer by blocking the action of Atoh1. Furthermore, when the Hic1 gene is methylated, it cannot do its job properly and formation of medulloblastoma occurs by overexpression of Atoh1.

With this specific information about the formation of medulloblastoma, therapeutics directly targeting this pathway are underway.

Currently there are treatments for other diseases which de-methylate genes and allow the gene products to function properly. There is hope that these same therapeutics will one day help to cure this aggressive childhood cancer.