How a protein breaks free to cause deadly cancers

Irvine, Calif., July 18, 2022 – Better treatments for some of cancer’s deadliest forms could be closer due to a University of California, Irvine-led discovery about how a certain protein is activated in tumor cells. The finding, spearheaded by researchers with the School of Biological Sciences, could eventually lead to possible therapies for the especially dangerous melanoma and pancreatic adenocarcinoma, as well as the most common type of childhood brain cancer and adult skin cancer. A paper describing the project appears in Life Science Alliance.

The discovery concerns the GLI1 protein, which is important in cell development but has also been found turned on in various cancers. GLI1 is typically activated by the Hedgehog signaling pathway, known as HH. However, scientists have known for about a decade that crosstalk, or interaction, between HH and the mitogen-activated protein kinase pathway has a role in cancers.

“In some cases, proteins in one pathway can turn on proteins in another,” said lead author A. Jane Bardwell, project scientist in UCI’s Department of Developmental and Cell Biology. “It’s a complex system. We wanted to understand the molecular mechanism that leads to GLI1 being activated by proteins in the MAPK pathway.”

GLI1 normally binds tightly with a protein called SUFU. That protein suppresses GLI1, preventing it from penetrating cell nuclei and turning on genes. The scientists examined seven sites on the GLI1 protein that could be phosphorylated, or have a phosphate group transferred onto it.

“We identified three that can be phosphorylated and are involved in weakening the binding between GLI1 and SUFU,” said Lee Bardwell, professor of developmental and cell biology whose laboratory conducted the project. “This process activates GLI1, enabling it to enter the nucleus of cells, where it can cause uncontrolled growth resulting in cancer.”

He noted that phosphorylation of all three sites causes a significantly higher level of GLI1 escape from SUFU than if just one or even two of them receive phosphate groups.

The discovery is a significant step toward more effective and personalized cancer treatments. “If we can understand exactly what is going on in a certain cancer or particular tumor, it could be possible to develop a drug specific to a specific tumor or individual patient,” Bardwell said. “It would allow us to treat these diseases without the toxicity of basic chemotherapy.” In addition, many tumors from the same cancer have different mutations among individuals. Eventually, it may be feasible to screen tumors to develop the best approach for each.

The research was performed in collaboration with the UCI School of Medicine’s Department of Microbiology & Molecular Genetics and the Stanford University School of Medicine’s Department of Dermatology. It was funded by the National Institute of General Medical Sciences, the National Cancer Institute, the UC Cancer Research Coordinating Committee and the Damon Runyon Cancer Research Foundation.

About UCI’s Brilliant Future campaign: Publicly launched on Oct. 4, 2019, the Brilliant Future campaign aims to raise awareness and support for UCI. By engaging 75,000 alumni and garnering $2 billion in philanthropic investment, UCI seeks to reach new heights of excellence in student success, health and wellness, research and more. The School of Biological Sciences plays a vital role in the success of the campaign. Learn more by visiting https://brilliantfuture.uci.edu/school-of-biological-sciences.

About the University of California, Irvine: Founded in 1965, UCI is the youngest member of the prestigious Association of American Universities and is ranked among the nation’s top 10 public universities by U.S. News & World Report. The campus has produced five Nobel laureates and is known for its academic achievement, premier research, innovation and anteater mascot. Led by Chancellor Howard Gillman, UCI has more than 36,000 students and offers 224 degree programs. It’s located in one of the world’s safest and most economically vibrant communities and is Orange County’s second-largest employer, contributing $7 billion annually to the local economy and $8 billion statewide. For more on UCI, visit www.uci.edu.

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