Researchers from Columbia University Medical Center’s Herbert Irving Comprehensive Cancer Center have identified a protein that activates brain stem cells to make new neurons – but that may be hijacked later in life to cause brain cancer in humans. The protein called Huwe1 normally functions to eliminate other unnecessary proteins and was found to act as a tumor suppressor in brain cancer.
These findings were co-led by Antonio Iavarone, M.D., associate professor of neurology and pathology and cell biology, and Anna Lasorella, M.D., assistant professor of pediatrics and pathology and cell biology, both of Columbia’s Institute for Cancer Genetics at the Herbert Irving Comprehensive Cancer Center.
“By identifying the normal function of Huwe1, we were able to learn that deregulation of Huwe1 function is involved in tumor development,” say Dr. Iavarone.
“This demonstrates that a gene’s basic function must be understood before we can learn how it also plays a role in the development of cancer,” says Dr. Lasorella.
During normal brain development, neural stem cells grow and divide rapidly before developing into neurons. To successfully change into neurons, they must remove all proteins that keep the cells in an immature, stem cell state. To understand how brain tumors develop, Drs. Iavarone’s and Lasorella’s teams decided that they needed to understand the development of normal neural stem cells. Their research demonstrated that Huwe1 is responsible for “crowd control” for the mechanism that regulates the stem cell mass in the developing brain – effectively weeding out unnecessary stem cell-specific proteins – and promoting neurogenesis. Without Huwe1, Dr. Lasorella discovered that in mice, too few mature neurons form in the brain, resulting in the brain failing to properly develop.
Because the stem cells and cancer cells share the capacity for rapid proliferation, but cancer cells have lost crowd control, Dr. Iavarone then looked for signs of Huwe1 alterations in human brain tumors. Compared to normal brain tissue, he found that Huwe1 activity in tumors was significantly lower than in normal brain tissue.
“The loss of Huwe1 may be an important factor in the development of brain cancer, suggesting that Huwe1 protein function may be used for new therapeutic targets to fight deadly brain cancer,” says Dr. Lasorella.
“Our next step will be to analyze the structural changes in Huwe1, and research ways to restore this gene in brain tumor patients,” says Dr. Iavarone. “In mice, giving Huwe1 back blocks the ability of normal stem cells to proliferate and develop tumors. We are hopeful that if we can restore Huwe1 activity in brain tumor cells resulting from Huwe1 deletion, then we can stop the tumor growth.”
Illustration: The image shows a cortical section from the brain of E18.5 mouse embryo in which the gene coding for the Huwe1 ubiquitin ligase was selectively deleted. Inactivation of Huwe1 leads to expansion of the neural stem cell compartment (blue nuclei), disruption of laminar patterning (Tbr1, pink), and impaired generation of neurons (MAP2, green). Superimposed onto the cortical section is the neural N-Myc-DLL3 molecular network. The network is aberrantly activated and is responsible for the phenotypic abnormalities triggered by loss of Huwe1. The same molecular events (inactivation of Huwe1 and deregulation of N-Myc) are selected during oncogenic transformation in the human brain. --Columbia University Medical Center.
Columbia University Medical Center Press Release (08/17/09)
Breakthrough Digest (08/18/09)
Science Daily (08/19/09)
Abstract (Developmental Cell, Volume 17, Issue 2, 210-221, 18 August 2009)