October 19, 2007

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: aliquots@vanderbilt.edu.

Brain size: What’s the buzz?

The disorder primary microcephaly — “small head” — can be caused by mutations in the human gene microcephalin (MCPH1). How this gene determines human brain size is a mystery, and clues are now coming from a seemingly unlikely source: the fruit fly.

In a genetic screen for regulators of the Drosophila embryonic cell cycle, Laura Lee, M.D., Ph.D., and colleagues identified mcph1, the fruit fly homolog of MCPH1. They report in the Oct. 15 issue of the Journal of Cell Science that fly embryos lacking mcph1 exhibit genomic instability and undergo cell-cycle arrest. The authors propose that the MCPH1 protein coordinates a cell-cycle transition in fly embryos: in the absence of MCPH1, the chromosomes condense before DNA replication is complete, resulting in arrest of nuclear division. They also note that adult male flies lacking mcph1 have defects in certain brain structures, suggesting an evolutionarily conserved role for MCPH1 in brain development.

— Leigh MacMillan

Estrogen’s harmful effects amplified

Although banned in industrial nations, the pesticides kepone, DDT and methoxychlor have a long half-life and may persist at low levels in the environment. Because of their estrogen-like activities, exposure to the compounds poses a potential hazard to the female reproductive system, possibly impairing fertility and sparking cancer.

To date, only high doses have been shown to have harmful estrogenic effects. In the October issue of Endocrinology, Sanjoy Das, Ph.D., and colleagues report that a protein found naturally in the body, called Bip, may amplify the harmful estrogenic effects of low doses of these “environmental estrogens” or xenoestrogens.

In mice with increased uterine Bip expression, kepone increased cellular proliferation, uterine weight and the expression of genes that control uterine growth. Such changes may make the uterus nonreceptive to embryo implantation and lead to uterine cancer. Also, since Bip expression is induced by stress, various stressors may increase one's susceptibility to the estrogenic effects of such compounds.

— Melissa Marino

Oncogene remodels cell structure

Synovial sarcoma, an aggressive soft tissue cancer that is resistant to current therapies, is associated with a rearrangement between chromosomes 18 and X. The translocation usually generates one of two fusion proteins, SYT-SSX1 or SYT-SSX2. SYT-SSX1 is a “classic” oncogene: it enhances cell proliferation and tumorigenicity.

Josiane Eid, M.D., and colleagues report in the October Molecular Biology of the Cell that SYT-SSX2 is a unique oncogene: it alters cellular architecture, causing cells to become elongated and extend projections. The investigators implicated the Eph/ephrin signaling pathway, particularly EphB2, in the cytoskeletal malformations and noted an Eph/ephrin-independent increase in the stability of the microtubule network, with accumulation of the protein Glu tubulin. They detected high levels of both EphB2 and Glu tubulin in human synovial sarcoma samples, supporting the clinical relevance of the findings. The authors suggest that Eph/ephrin signaling and other pathways that contribute to cytoskeletal remodeling may represent therapeutic targets for synovial sarcoma.

— Leigh MacMillan

ABCs of multi-drug transport

All cells — bacterial to human — have built-in defense mechanisms that eject toxic compounds through a pump in the cell membrane. Expression of these pumps, however, can lead to resistance to antibiotics and chemotherapy drugs.

To elucidate the mechanisms of a class of pumps called ABC (ATP-binding cassette) transporters, Hassane Mchaourab, Ph.D., and colleagues introduced molecular probes into an ABC transporter called MsbA. They then tracked the probes to determine how the different domains of MsbA move relative to each other during the transport of a molecule across an artificial cell membrane. In the October edition of PLoS Biology, the investigators report that ATP hydrolysis, the chemical reaction that fuels transport, results in a nearly 30 Å movement of these domains — a large distance at a molecular level.

Understanding the structural mechanics of such transport may help illuminate the mechanisms of drug resistance and guide the design of new antibiotics and chemotherapeutics able to overcome these transporters.

— Melissa Marino

Past Aliquots

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