October 24, 2008

Aliquots — Research highlights from VUMC laboratories

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Twisted tongues mean troubled palates

Cleft palate – an opening in the roof of the mouth – is one of the most common birth defects in humans. Before it is treated surgically, it can interfere with feeding, speech development and hearing.

Previous studies have pointed to both reduced and excessive activity of the signaling protein Shh in the pathogenesis of cleft palate. Chin Chiang, Ph.D., and colleagues examined the role of a member of the Shh signaling pathway, Gli3. They report in the October Developmental Dynamics that mice lacking Gli3 had a high incidence of cleft palate, but that several measures of palate development – neural crest cell migration, palatal shelf cell proliferation, key signaling components – were unaffected in these mice. Interestingly, the tongues in Gli3 knockout mice with cleft palates were often misshapen, tilted, or failed to descend, implicating Gli3 in tongue development. The researchers showed that palatal shelf tissue cultured in the absence of tongue could fuse, suggesting that an abnormal tongue impedes palate formation.

— Leigh MacMillan

Going upstream in the genome

Genomics technologies have helped identify downstream targets of transcription factors – the genes they turn on/off or up/down. But identifying the upstream pathways that regulate transcription factor activity has been more challenging.

The p53 family of transcription factors, which includes p63 and p73, plays an important role in tumor suppression, with p53 being lost in more than half of all tumors. Because p73 can regulate many p53 target genes – including those that instruct tumor cells to commit “suicide” – p73 modulators may provide promising leads for cancer therapies.

Jennifer Pietenpol, Ph.D., Jennifer Rosenbluth, and colleagues generated a “signature” of genes expressed downstream of p73 and then compared this gene signature to drug-related profiles in a publicly available database. In the October issue of Molecular and Cellular Biology, they identify mammalian Target of Rapamycin (mTOR) as a potential regulator and found that mTOR inhibitors increased p73 levels in normal and cancer cells in culture. In addition to identifying a potential therapeutic target, the research suggests a novel approach to identifying upstream regulators of transcription factors.

— Melissa Marino

Come together, right now…chemically

Embryonic development, immune cell response, and even cancer metastasis involve chemotaxis, the directed movement of cells toward a particular “attractive” chemical (chemoattractant).

Chang Chung, Ph.D., and colleagues are studying the mechanisms of chemotaxis in Dictyostelium, amoeba-like cells that normally live independently in the soil. When their food source becomes depleted, a single Dictyostelium cell sends out chemical stress signals that attract the other cells, resulting in their aggregation into a large, slug-like organism. The researchers examined how alterations in a key cell signaling pathway – the PI3K/PTEN pathway – affect a cell’s ability to sense and respond to chemoattractant gradients.

In the Oct. 15 issue of Biophysical Journal, they report that when this pathway is impaired, a cell’s speed and accuracy toward the chemical gradient are less coordinated. Intact signaling helps coordinate the cell’s speed and accuracy, making chemotaxis more efficient. Because this coordination is likely to be universal for chemotactic cells, the findings could reveal important clues to how this process is regulated in human cells.

— Melissa Marino

Salt in the diet ups its own excretion

The effects of dietary salt on blood pressure are complex. A high-salt diet increases levels of cyclooxygenase-2 (COX-2) protein in the kidney, and inhibition of COX-2 increases blood pressure. Both findings suggest that COX-2 works to maintain normal blood pressure in a high-salt setting.

Chuan-Ming Hao, M.D., Ph.D., and colleagues have now characterized the specific prostaglandin product that contributes to COX-2’s anti-hypertensive effect. They show that mice fed a high-salt diet have increased levels of prostaglandin E2 (PGE2) and the enzyme responsible for its synthesis, prostaglandin E synthase 1, in the medulla region of the kidney. They further demonstrate that PGE2 acts through the EP2 receptor to increase urine volume and urinary sodium excretion. The findings, reported in the September American Journal of Physiology – Renal Physiology, suggest that the COX-2/PGE2/EP2 pathway in the kidney medulla plays an important role in maintaining body sodium balance and systemic blood pressure.

— Leigh MacMillan

Past Aliquots

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