Navigation Links
St. Jude researchers find key step in programmed cell death

Investigators at St. Jude Childrens 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 papers 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 Kostmanns 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 Parkinsons 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 cytokinessmall proteins used by neurons and blood-borne cells to communicate messagescontribute 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 mitochondriatiny chemical packets that serve as the main energy source for cells. HtrA2 is made in the cells 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.


Contact: Carrie Strehlau
St. Jude Children's Research Hospital

Related medicine news :

1. Mayo Researchers Look for Explanation Behind High Incidence of Diabetes Among Asian Indians
2. Mayo researchers look for explanation behind high incidence of diabetes among Asian Indians
3. UT Southwestern researchers investigate predictors for sickle-cell-anemia complications
4. Researchers find possible target to treat deadly bloodstream infections
5. Rutgers researchers unlock mysteries of vitamin A metabolism during embryonic development
6. U of Minn researchers discover genetic cancer link between humans and dogs
7. New genetic association with schizophrenia found by researchers
8. Thomson Scientific To Honor Australias Top Researchers With Dedicated Australian Research Day
9. This is your brain on jazz: researchers use MRI to study spontaneity, creativity
10. First look: Princeton researchers peek into deepest recesses of human brain
11. U of Minn researchers find primary alcohol prevention programs are needed for tweens
Post Your Comments:
(Date:11/25/2015)... ... ... Dr. John Pierce, Medical Director at the Ageless Forever clinic in Las ... Pro laser therapy cap. FDA cleared for safety and efficacy, the Capillus272 offers men ... surgery, prescription pills, or topical foams. , “Capillus272™ Pro is a home-use device ...
(Date:11/25/2015)... ... November 25, 2015 , ... For the first time, ... Two Organizations, One Beat ” campaign. The partnership between the two groups began in ... in MAP International’s cause. , MAP International was founded in 1954 and is an ...
(Date:11/25/2015)... ... November 25, 2015 , ... Dental professionals who would ... OH , are invited to attend Dr. Mark Iacobelli’s Advanced Implant Mentoring (AIM) CE ... Cleveland, OH. , As the co-founders of Advanced Implant Mentoring (AIM), Dr. Iacobelli ...
(Date:11/25/2015)... ... 25, 2015 , ... The McHenry County law firm of Botto Gilbert ... Attorneys Francisco J. Botto and Alex C. Wimmer. Attorneys Botto and Wimmer represented the ... App (2d) 130884WC. , According to court documents, Adcock testified that on May 10, ...
(Date:11/25/2015)... ... November 25, 2015 , ... SCOTTSDALE, AZ) ... plastic surgeon specializing in both surgical and non-surgical treatments, announced the expansion of ... Hobgood Facial Plastic Surgery. , Highly trained and nationally recognized for his ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... , November 26, 2015 /PRNewswire/ ... announced the addition of the  "2016 ... the Global Cell Surface Testing Market: ... report to their offering.  --> ... addition of the  "2016 Future Horizons ...
(Date:11/26/2015)... --> ... att använda SyMRI för att hitta optimal ... med multipel skleros (MS) eller hjärntumörmetastaser och ... för att kunna använda SyMRI Research Edition ... kan man generera flera konstrastbilder från en ...
(Date:11/26/2015)... , November 26, 2015 ... the addition of the  "2016 Future ... European Therapeutic Drug Monitoring (TDM) Market: ... Intelligence, Emerging Opportunities"  report to their ... has announced the addition of the  ...
Breaking Medicine Technology: