Tag Archives: Gene

‘Mystery gene’ matures the skeleton of the cell

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“I’m a professional pin-in-a-haystack seeker,” geneticist Thijn Brummelkamp responds when asked why he excels at tracking down proteins and genes that other people did not find, despite the fact that some have managed to remain elusive for as long as forty years. His research group at the Netherlands Cancer Institute has once again managed to track down one of these “mystery genes” – the gene that ensures that the final form of the protein actin is created, a main component of our cell skeleton.

Cell biologists are very interested in actin, because actin – a protein of which we produce more than 100 kilograms in our lifetime – is a main component of the cell skeleton and one of the most abundant molecules in a cell. Large quantities can be found in every cell type and it has many purposes: it gives shape to the cell and makes it firmer, it plays an important role in cell division, it can propel cells forward, and provides strength to our muscles. People with faulty actin proteins often suffer from muscle disease. Much is known about the function of actin, but how the final form of this important protein is made and which gene is behind it? “We didn’t know,” says Brummelkamp, whose mission is to find out the function of our genes.

Multi-purpose method for genetics in human cells
Together with other researchers, Brummelkamp uses this multi-purpose method to find the genetic causes of particular conditions. He has already shown how the Ebola virus and a number of other viruses, as well as certain forms of chemotherapy, manage to enter a cell. He also investigated why cancer cells are resistant to certain types of therapy and discovered a protein found in cancer cells that acts as a brake on the immune system. This time he went looking for a gene that matures actin – and as a result, the skeleton of the cell.

Microscopy image of actine. (Actine is yellow, cell core is blue)/CREDIT:Peter Haarh, Netherlands Cancer Institute

In search of scissors
Before a protein is completely “finished” – or mature, as the researchers describe it in Science – and can fully perform its function in the cell, it usually has to be stripped of a specific amino acid first. This amino acid is then cut from a protein by a pair of molecular scissors. This is also what occurs with  actin. It was known on which side of the actin the relevant amino acid is cut off. However, no one managed to find the enzyme that acts as scissors in this process.

Peter Haahr, postdoc in Brummelkamp’s group, worked on the following experiment: first he caused random mutations (mistakes) in random haploid cells. Then he selected the cells containing the immature actin by adding a fluorescently labeled antibody to his cells that fit in the exact spot where the amino acid is cut off. As a third and final step, he investigated which gene mutated after this process.

They called it ‘ACTMAP’
Then came the “eureka”-moment: Haahr had traced down the molecular scissors that cut the essential amino acid from actin. Those scissors turned out to be controlled by a gene with a previously unknown function; one no researcher had ever worked with. This means that the researchers were able to name the gene themselves, and they settled on ACTMAP (ACTin MAturation Protease).

More scissors found in the skeleton of the cell
ACTMAP is not the first mystery gene discovered by Brummelkamp that plays a role in our cell skeleton function. Using the same method, his group has been able to detect three unknown molecular scissors over recent years that cut an amino acid from tubulin, the other main component of the cell skeleton. These scissors allow tubulin to perform its dynamic functions properly inside the cell. The last scissors (MATCAP) were discovered and described in Science this year. Through this earlier work on the cell skeleton, Brummelkamp managed to arrive at actin.

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Breast Cancer-Causing Gene Identified

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Breast Cancer-Causing Gene Identified

A gene called GT198, known for its ability to repair DNA, is actually causing breast cancer, found scientists hoping that it may help in diagnosing breast cancer early, said Dr. Lan Ko, cancer biologist in the Department of Pathology at the Medical College of Georgia at Augusta University and at the Georgia Cancer Center at AU.

Mutations of the gene are known to be present in both early onset breast and ovarian cancer. Now scientists have shown that the stem, or progenitor cells, which should ultimately make healthy breast tissue, can also have GT198 mutations that prompt them to instead make a perfect bed for breast cancer.

Their studies, published in the American Journal of Pathology, were done on an international sampling from 254 cases of breast cancer in pre- and postmenopausal women.

"This gene mutation can be in both the blood and the tumor tissue of patients, and in the tissue, it’s in high percentages," said Ko, the study’s corresponding author. "We believe that once this gene is mutated, it induces the tumor to grow."

GT198, which is also a coactivator of receptors for steroid hormones such as estrogen, is normally regulated by estrogen, Ko said. But once mutated, GT198 can enable tumor production without estrogen. "Regardless of how much hormone you have, it’s out-of-control growth," Ko said of the resulting classic, rapid growth of cancer.

In a cancerous breast, scientists have seen the problems with the various components of breast tissue but could not fully explain why they happened. The tissue, called the stroma, includes fat cells, or adipocytes, that provide padding; fibroblasts, which make the framework for tissue; pericytes in blood vessels, which are contractile cells that help regulate blood pressure; as well as myoepithelial cells comprising the outer layer of the ductal system through which milk flows.

The new study backs up a few steps and shows that mutated GT198 also directly affects stem cells found on blood vessels that make these various components of breast tissue. "This puts it together," Ko said.

"It’s a new target in cancer. It’s very exciting," said Dr. Nita Maihle, MCG cancer biologist, associate center director for education at the university’s Cancer Center and a study co-author. "This tells you that all the different types of stromal cells in breast tissue are affected by the GT198 mutation because they all come from a common progenitor cell."

Ko first cloned the human GT198 gene while a postdoctoral fellow at Harvard Medical School. All cells have the GT198 gene but most adult cells don’t express it. In the breast, for example, it may be transiently expressed in a pregnant woman preparing for milk production and, potentially, in the case of breast injury. Males express it in the testes.

Ductal breast cancer, which is in the ducts that carry milk, is the most common type of breast cancer and lobular carcinoma, which begins in the milk-producing glands, is the second most common. Most breast cancer comes from the cells that line those ducts, Maihle said.

BRCA1 and 2, genes whose proteins are supposed to work as tumor suppressors and also repair DNA damage, were the first known risk factor genes for familial breast cancer as well as ovarian and other cancers. About 4 percent of familial breast cancers would include inherited mutations of GT198, which is also considered a causative gene in sporadic cases, Ko said.

[tags, breast cancer, cause, gt198 gene, cause behind breast cancer, isolated]