By David N. Leff

Editor¿s note: Science Scan is a roundup of recently published biotechnology-relevant research.

Tumor-suppressor genes were themselves suppressed when two oncogenes, c-myc and Wnt-1, kicked in. But two other cancer-protective genes, neu and ras, stuck by their tumor-suppressing guns. This drama unfolded in transgenic mice afflicted with a proneness to incur breast cancer, and deprived of cyclin D1 ¿ one of many proteins involved in cell-division machinery. Most human breast tumor cells overexpress cyclin D1.

A paper in Nature dated June 28, 2001, reports this phenomenon under the title: ¿Specific protection against breast cancers by cyclin D1 ablation.¿ Its authors, cell biologists, are at the Harvard-affiliated Dana-Farber Cancer Institute in Boston. An accompanying commentary raises the question: ¿Are all cancer genes equal?¿

When mammalian cells turn malignant, they scramble to ¿silence,¿ or lose, the guardian tumor-suppressing oncogenes that keep healthy cells healthy. Mutation or overexpression turns these proto-oncogenes hyperactive. This genetic hijacking tends to vary from one bodily tissue to another ¿ a fact that has puzzled research oncologists.

The cyclin D1 gene is amplified in up to 20 percent of human breast cancers, while the protein it expresses, cyclin D1, is overexpressed in more than half of human mammary carcinomas ¿ including their metastases. This overexpression suggested to the Nature paper¿s co-authors that the excess cyclin D1 might cause, as well as stimulate, the disease. Their transgenic mice, engineered to overexpress the protein in mammary glands, succumbed to breast cancers.

Whereupon, the team asked whether getting rid of the cyclin D1 protein might protect the cyclin D1 gene lacking in those mice against the cancers. So they cross-bred their cyclin D1-deficient rodents with four other groups of mice, each modified to express a different oncogene known to cause breast cancer. Their results implied that in breast epithelium, Neu and Ras promote cell proliferation only by inducing expression of cyclin D1, while Myc and Wynt do their job through other cell-cycle targets.

The authors conclude: ¿Our results suggest that an anti-cyclin D1 therapy might be highly specific in treating human breast cancers with activated Neu-Ras pathways.¿

Puzzling Upsurge Of Insulin ¿ As Its Resistance Marks Diabetes Onset ¿ Still To Be Elucidated

Bacterial drug resistance to antibiotics is a mounting menace to infectious disease management. There¿s another resistance factor in which the ¿drug¿ is insulin, which the body secretes to manage its glucose and energy balance. In Type II diabetes mellitus, as well as in obesity, high blood pressure, hyperlipidemias and endocrine disorders, the body develops resistance to its own insulin.

Insulin originates in the pancreatic islets of Langerhans, which harbor the beta cells that actually generate the hormone. When insulin resistance sets in, these beta cells compensate for the new deficiency by expanding its secretory capacity, and/or their own size and volume. This mitigation of the resistance can go on for a long time, before the waning insulin finally fails.

Researchers at Harvard¿s Joslin Diabetes Center in Boston wondered whether some growth factor in the blood, independent of glucose and obesity, might be responsible for this prolonged surcease from the resistance ¿ islet hyperplasia. To test this hypothesis, they transplanted wild-type (WT) islets under the kidney capsules of healthy, lean mice, and into obese, hyperglycemic ob/ob mice.

Eight weeks after transplantation ¿ during which the mice gained considerable body weight ¿ they removed and measured recovered islets. Overall, they discerned a significant increase in graft thickness and surface area, resulting in increased beta-cell volume.

The co-authors did not identify the exact nature of the presumed circulating growth factor, or what tissue serves as its source. They speculated that the factor might be insulin itself, and observed: ¿Further studies will be needed to determine the specific beta-cell growth factor and the potential role of insulin in mediating this important biological feedback mechanism.¿ Their PNAS paper concludes: ¿Identification of this factor might be of great therapeutic potential in reversing beta-cell loss in Type I diabetes or stimulating islet growth for transplantation into humans with diabetes.¿

Laser Light Galvanizes ¿Caged¿ (Inactivated) Cells Into Resuming Dormant Locomotion

True or false? Most cells in the body ¿ not counting blood cells ¿ stay put in one place their entire lives, just as whole plants do.

The answer: false. Those microscopic, living cellular structures move a little or a lot ¿ healing wounds, developing embryos, scouting and attacking disease-causing invaders, sometimes spreading cancer. How cells get themselves from one place to another raises intriguing chemical and mechanical questions.

One novel answer relies on laser light and fish scales. The Journal of Cell Biology, dated May 28, 2001, tells that story in a research article titled: ¿Local photorelease of caged thymosin b4 in locomoting keratocytes causes cell turning.¿ Its senior author is cell biologist Ken Jacobson at the University of North Carolina at Chapel Hill.

Using a beam of laser light only a few microns in diameter, the co-authors succeeded ¿ for the first time ¿ in getting that beam to alter the course of a moving cell. The laser activated thymosin proteins from what are called ¿caged¿ proteins they had introduced into cells derived from fish scales. They are somewhat similar to human skin cells. Caging is a process that makes cells in motion less active.

Then they aimed the laser light into parts of the cell to break the bond between the caging group and the amino acid, to reactivate the protein. Thereupon, depending on where they shined the light, cells rotated by as much as 90 degrees.

¿We think this opens a lot of possibilities,¿ Jacobson observed, ¿for learning what many signaling molecules do inside cells. If you can understand the behavior of an internal protein, then you can make inhibitors or promoters that have implications for drug discovery. In some cases, such as formation of new blood vessels in treating coronary artery disease, you might want to speed up cell movement. On the other hand, you¿d want to stop movement of cancer cells.¿

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