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Ever since she was a postdoctoral fellow in the laboratory of the late Stanley Korsmeyer, Nika Danial, PhD, has been intrigued with BAD (BCL-2 associated death promoter), a member of the BCL-2 family of proteins known to regulate apoptosis, a process that many cancer cells escape. Like an alert sentinel, BAD senses cellular damage and communicates this information to the mitochondria, which in turn, release apoptogenic factors leading to destruction of the damaged cell. But, Danial was curious about the biology of BAD and whether the protein might play a nonapoptotic role in healthy cells.
She and colleagues embarked upon a series of biochemical studies of the proteins to which BAD binds at mitochondria, she says, and "literally stumbled" upon glucokinase (GK, an enzyme that facilitates phosphorylation of glucose), suggesting a new role for BAD in the metabolism of glucose. Moreover, genetic experiments showed that mice lacking the BAD protein had fasting hyperglycemia and impaired glucose tolerance, features characteristic of type 2 diabetes.
This startling discovery led to a series of experiments to figure out how BAD toggles between its two functions. To their surprise, the BH3 domain of BAD controls both apoptosis and glucose metabolism, says Danial, now assistant professor in the Department of Cancer Biology. Like a master switch, the phosphorylation status of the BH3 domain regulates the ligands to which BAD can bind and, thereby, determines whether the cell signals through the apoptotic or the metabolic pathway. When investigators created a genetic mutant of BAD whose BH3 domain could not be phosphorylated, the mutant could bind only to its pro-apoptotic partners and proved incompetent for metabolic function, explains Danial. Conversely, a genetic mutant whose BH3 domain was constitutively phosphorylated could bind only to GK, required for glucose metabolism, and could not induce apoptosis.
These unusual findings sparked a new idea. "If we could mimic the phosphorylated BH3 domain through genetic or pharmacologic maneuvers," explains Danial, "we could stimulate BAD's metabolic function without sensitizing cells to apoptosis." To test this hypothesis, Danial's laboratory collaborated with Loren Walensky, MD, PhD, of the Department of Pediatric Oncology, who turned the amino acid sequence of the constitutively phosphorylated BH3 domain of BAD into a peptidemimetic compound. Danial's lab then tested the compound in defective beta cells of the pancreas, which in type 2 diabetes become incapable of secreting insulin in response to glucose. Strikingly, the compound restored glucose metabolism and insulin secretion in the faulty cells. "This demonstrates that the BH3 domain is not only required, but also sufficient for BAD's function in glucose homeostasis," Danial emphasizes. "And, remarkably, it opens up a whole new therapeutic strategy for diabetes based on mimicking the function of a domain that nature has already designed to activate GK."
Ongoing animal model studies using both genetic and pharmacologic manipulations of BAD's metabolic function are beginning to show promise as well. The mimetic compounds that emerged from this collaboration between biologists and chemists have the potential to serve a dual therapeutic purpose, observes Danial. "They may help control blood glucose while preventing apoptosis in the cell," thus eliminating some toxicity problems. "We hope this novel therapeutic strategy will have significant implications for type 2 diabetes."
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