Scientists Identify Novel Link Between Cellular Growth and Metabolism

A team of Miller School of Medicine researchers, working with investigators from three other institutions, has identified a relationship between a family of lipid modifications of a growth factor, and how that growth factor may regulate cellular fate and growth. This discovery may begin to show how the function of these proteins is modified by metabolic activity in both developmental and disease settings, such as cancer and diabetes.

Their findings have been published in Cell Reports in an article titled “Identification of a family of fatty acid-speciated Sonic Hedgehog proteins, whose members display differential biological properties.”

The researchers studied the Hedgehog family of proteins, which play a variety of biological roles. Modifications in these proteins have been implicated in a large number of human developmental disorders, and appear necessary for the viability of many cancers. More recently, it had been suggested that Hedgehog proteins also function as hormones to link nutritional status to cellular growth. Prior to this research, however, a mechanistic way for Hedgehog proteins to provide this function was unknown.

“We began this work because we noticed that when Hedgehog proteins were produced under different cellular conditions, their ability to be secreted in their physiologically relevant form was altered,” said senior author David J. Robbins, Ph.D., professor of surgery in the DeWitt Daughtry Family Department of Surgery’s Division of Surgical Oncology. “We therefore purified the Hedgehog protein, Sonic Hedgehog, from cells grown under different conditions.

“Surprisingly, we noticed that Sonic Hedgehog was actually present in these cells as a family of proteins modified by a large group of lipids, and that these modifications on Sonic Hedgehog were dramatically different when the cells expressing them were grown in different ways. These modifications occur when specific enzymes add fatty acids to Hedgehog proteins, increasing their activity and promoting cellular growth.”

The next step for the researchers will be identifying specific modification-related functions in different developmental and disease settings, and determining if those functions can be inhibited. Successfully doing so could open the door to possible new treatments for metabolic related human pathologies, including cancer.

Additional Miller School authors of the journal article include first author Jun Long, a Ph.D. candidate in the Molecular Oncology Research Program; Jezebel Rodriguez-Blanco, Ph.D., a post-doctoral fellow in Dr. Robbins’ laboratory; and Anthony J. Capobianco, Ph.D., professor of surgery and Director of the Molecular Oncology Research Program.

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