March 21, 2008

Aliquots — Research highlights from VUMC laboratories

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We welcome suggestions for research to highlight in Aliquots. The items should be primary research articles (no reviews, editorials or commentaries) published within the last two months in a peer-reviewed journal. Please send the article citation (PDF if available) and any other feedback about the column to:

A vivid new view of DNA repair

Radiation, chemicals and other naturally occurring assaults bombard our DNA daily, often resulting in double-strand breaks in our DNA molecules that can spark cell death or cancer. Luckily, cells have error-correcting pathways to patch these breaks. The DNA-dependent protein kinase catalytic subunit (DNA-PKcs) is a key player in one such repair process, the nonhomologous end joining pathway.

Phoebe Stewart, Ph.D., Dewight Williams Ph.D., and colleagues have obtained the most detailed 3-dimensional structure of this enzyme to date. The 7-angstrom resolution structure — featured on the cover of the March Structure — reveals features of the protein complex not previously visible. With this detailed structural information, the investigators identified a potential DNA-binding site in the molecule and propose a model for how DNA and other enzymes interact with this molecule.

This work sets the stage for building up more complex structures containing this enzyme and the other components of the pathway — elements required for understanding this essential DNA repair process.

— Melissa Marino

Boning up with Wnts

Myeloma bone disease is an incurable malignancy characterized by impaired bone resorption and formation, a process regulated by bone-forming osteoblasts and bone-resorbing osteoclasts. Increasing evidence shows that the Wnt signaling pathway plays a critical role physiologically in regulating bone mass and pathologically in myeloma bone disease.

Claire Edwards, Ph.D., and colleagues address the role of Wnt signaling in the development of myeloma bone disease in the March issue of Blood. Using a well-characterized mouse model of myeloma that closely reflects human disease, they found that increasing Wnt signaling directly in the bone microenvironment induces osteoblasts to form bone, indirectly reducing tumor burden. However, increasing Wnt signaling at sites other than bone induces tumor growth, raising concern for generating therapies that enhance Wnt signaling as a treatment for myeloma bone disease.

The results suggest that tumor cell response to Wnt signaling is highly dependent on microenvironment, raising questions about xenograft models and emphasizing the importance of appropriate in vivo approaches to study multiple myeloma.

— Susanne Tranguch

Poor baby antibodies

Infants can mount an immune response to viruses and vaccines, but the activity of their antibodies is much weaker than those of adults. The basis for this difference in antibody quality is not clear.

Previously, James Crowe Jr., M.D., and colleagues found that both adults and infants use the same variable gene segment (called VH1-46) to produce antibodies to rotavirus, the most important viral cause of dehydrating diarrhea in infants and young children. However, the adult gene segment encoding this antibody contains far more mutations than the same gene segment in infants.

In the March Journal of Immunology, the researchers report the structural and functional consequences of these mutations in the rotavirus-induced antibody response. They found that the adult mutations enhanced binding of the antibody to viral particles and caused the two to remain associated longer, resulting in a more potent antibody response. The results offer a molecular basis for the poor quality of infant antibodies made following virus infection or vaccination.

— Melissa Marino

Double trouble in kidney disease

The two forms of polycystic kidney disease — autosomal dominant (ADPKD) and autosomal recessive (ARPKD) — have different clinical profiles and are usually considered distinct diseases. Guanqing Wu, M.D., Ph.D., and colleagues now show that the two diseases share a common mechanism.

ARPKD is caused by mutation in the gene Pkhd1, which encodes the protein FPC. To study the disease mechanisms, the researchers created a mouse with a mutation in Pkhd1 and examined the relationship between FPC and another protein, PC2, which is mutated in the more common ADPKD.

In the March Journal of the American Society of Nephrology, they show that Pkhd1-deficient mice exhibit increased cyst formation, fewer cilia in renal tubules, and decreased PC2 activity, suggesting that FPC acts upstream to regulate PC2 function. Mice with mutations in both proteins had more severe renal cystic disease than mice with either single mutation, suggesting that FPC may modify disease severity and that the two causal gene products for ADPKD and ARPKD share a common pathogenic pathway.

— Susanne Tranguch

Past Aliquots

June 22, 2012
June 8, 2012
May 11, 2012
April 27, 2012
April 13, 2012
March 30, 2012
March 16, 2012