|
St. Jude researchers find key step in programmed cell death
March 03, 2008The discovery provides insight into how certain proteins, including Hax1, work and how they control the process of apoptosis
Investigators at St. Jude Children's Research Hospital have discovered a dance of proteins that protects certain cells from undergoing apoptosis, also known as programmed cell death. Understanding the fine points of apoptosis is important to researchers seeking ways to control this process.
In a series of experiments, St. Jude researchers found that if any one of three molecules is missing, certain cells lose the ability to protect themselves from apoptosis. A report on this work appears in the advance online publication of "Nature."
"This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis," said James Ihle, Ph.D., the paper's senior author and chair of the St. Jude Department of Biochemistry. "It provides incredible insights into how three proteins work and how they can control apoptosis."
The molecular interactions that St. Jude researchers describe in "Nature" play out in nerve cells and blood cells that develop from hematopoietic (blood-forming) stem cells.
A research team elsewhere recently reported that Kostmann's syndrome, a potentially fatal inherited deficiency of granulocytes in children, caused by excessive apoptosis of granulocytes, results from a deficiency in one of the three proteins, called Hax1.
"This suggests that the protein is playing basically the same role in humans as we described in mice," Ihle said.
Apoptosis rids the body of faulty or unneeded cells. However, molecular malfunctions that trigger apoptosis may cause some diseases, including Parkinson's disease. Understanding the biochemical interactions that control the extent of programmed cell death could lead to new treatments.
St. Jude biochemists have long studied how cytokines-small proteins used by neurons and blood-borne cells to communicate messages-contribute to keeping cells alive. For example, they demonstrated earlier that most cytokines controlling hematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.
In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.
"That was intriguing because several studies suggested that Hax1 was controlled by cytokine signaling," Ihle said. "Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis."
To pursue this lead, the researchers genetically engineered mice that lacked the gene for Hax1. The results showed that apoptosis in the animals' brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks. Second, apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.
"That additional window of survival is extremely important because in the body, cytokines are limiting." Ihle said. "The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl."
Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria-tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell's cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.
In lymphocytes, members of the Bcl-2 family of proteins both protect and initiate apoptosis. For this reason, Ihle and the researchers explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. This led them to discover that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur. This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.
St. Jude Children's Research Hospital
"This is probably the first description of what is happening mechanistically that contributes to the ability of cells to delay apoptosis," said James Ihle, Ph.D., the paper's senior author and chair of the St. Jude Department of Biochemistry. "It provides incredible insights into how three proteins work and how they can control apoptosis."
The molecular interactions that St. Jude researchers describe in "Nature" play out in nerve cells and blood cells that develop from hematopoietic (blood-forming) stem cells.
A research team elsewhere recently reported that Kostmann's syndrome, a potentially fatal inherited deficiency of granulocytes in children, caused by excessive apoptosis of granulocytes, results from a deficiency in one of the three proteins, called Hax1.
"This suggests that the protein is playing basically the same role in humans as we described in mice," Ihle said.
Apoptosis rids the body of faulty or unneeded cells. However, molecular malfunctions that trigger apoptosis may cause some diseases, including Parkinson's disease. Understanding the biochemical interactions that control the extent of programmed cell death could lead to new treatments.
St. Jude biochemists have long studied how cytokines-small proteins used by neurons and blood-borne cells to communicate messages-contribute to keeping cells alive. For example, they demonstrated earlier that most cytokines controlling hematopoietic cells require an enzyme called Jak2, or Jak3 in lymphocytes, at the receptors where cytokines attached to the cell.
In screening for components that are regulated by the Jak enzymes, the St. Jude team found the Hax1 protein.
"That was intriguing because several studies suggested that Hax1 was controlled by cytokine signaling," Ihle said. "Also, studies have suggested that if you overexpressed Hax1 in cells, the cells were protected from undergoing apoptosis."
To pursue this lead, the researchers genetically engineered mice that lacked the gene for Hax1. The results showed that apoptosis in the animals' brain caused extensive nerve cell degeneration that killed the mice within 10 to 12 weeks. Second, apoptosis in immune-system lymphocytes occurred in the altered mice eight hours sooner than in those with the Hax1 gene, when limited amounts of cytokines were available.
"That additional window of survival is extremely important because in the body, cytokines are limiting." Ihle said. "The key observation was that Hax1 was important in helping cells to survive. Importantly, what happened to the mice we generated was remarkably similar to what happens if you remove the mitochondrial enzymes called HtrA2 or Parl."
Exploring the similarities, the investigators found that Hax1 and Parl pair up in the inner membrane of the mitochondria-tiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cell's cytoplasm and is transported into the mitochondria, where the enzyme must have a region removed for it to be active. This requires snipping away 133 amino acids, the building blocks of proteins. The St. Jude researchers demonstrated that it is the Hax1/Parl pair that positions HtrA2 to allow the precise snipping that is required. Without Hax1, the snipping does not occur and HtrA2 remains inert.
In lymphocytes, members of the Bcl-2 family of proteins both protect and initiate apoptosis. For this reason, Ihle and the researchers explored this family of proteins to understand why lymphocytes needed an active HtrA2 mitochondrial enzyme. This led them to discover that if active HtrA2 were present, the incorporation of a protein called Bax into the mitochondrial outer membrane did not occur. This was significant since accumulation of Bax in the outer mitochondrial membrane allows the release of proteins that set off a chain of biochemical reactions, including the activation of enzymes that are responsible for cell death.
St. Jude Children's Research Hospital
Apoptosis News and Current Apoptosis Events RSSHIV conquers immune system faster than previously realized
New research into the earliest events occurring immediately upon infection with HIV-I shows that the virus deals a stunning blow to the immune system earlier than was previously understood.
Blue light used to harden tooth fillings stunts tumor growth
A blue curing light used to harden dental fillings also may stunt tumor growth, Medical College of Georgia researchers say.
Nerve cells derived from stem cells and transplanted into mice may lead to improved brain treatments
Scientists at the Burnham Institute for Medical Research have, for the first time, genetically programmed embryonic stem (ES) cells to become nerve cells when transplanted into the brain, according to a study published today in The Journal of Neuroscience.
Refusal of suicide order: Why tumor cells become resistant
Cells with irreparable DNA damage normally induce programmed cell death, or apoptosis. However, this mechanism often fails in tumor cells so that transformed cells are able to multiply and spread throughout the body.
Clinical study shows biological and clinical activity in relapsed leukemia patients
Finbarr Cotter, M.D., Ph.D., Professor of the Institute of Cell and Molecular Science at Barts and The London School of Medicine, today presented in an oral session "Clinical Caspase Activation in CLL by GCS-100: a Phase 2 Study" at the 10th International Conference on Malignant Lymphoma (10-ICML).
Synthetic molecules hold promise for new family of anti-cancer drugs
Synthetic molecules designed by two Hebrew University of Jerusalem researchers have succeeded in reducing and even eliminating the growth of human malignant tissues in mice, while having no toxic effects on normal tissue.
Fruits, vegetables and teas may protect smokers from lung cancer, UCLA researchers report
Tobacco smokers who eat three servings of fruits and vegetables per day and drink green or black tea may be protecting themselves from lung cancer, according to a first-of-its-kind study by UCLA cancer researchers.
Researchers explore the emerging role of infection in Alzheimer's disease
A number of chronic diseases are in fact caused by one or more infectious agents. For example, stomach ulcers are caused by Helicobacter pylori, chronic lung disease in newborns and chronic asthma in adults are both caused by Mycoplasmas and Chlamydia pneumonia, while some other pathogens have been associated with atherosclerosis.
Major 'missed' biochemical pathway emerges as important in virtually all cells
A new study by Duke University researchers provides more evidence that the nitric oxide (NO) system in the life of a cell plays a key role in disease, and the findings point to ways to improve treatment of illnesses such as heart disease and cancer.
A potential route for human tumor gene therapy
The type 1 Na+/H+ exchanger (NHE1) is a transmembrane protein found in all eukaryotic cells. One of its functions is to evacuate excessive H+ in the cytoplasm by means of Na+-H+ exchange, resulting in stable intracellular pH value.
More Apoptosis News Articles
| © 2008 BrightSurf.com |