Researchers at UT Southwestern Medical Center have made significant strides in cancer research by unveiling the structure of a critical protein known as midnolin. This discovery, made using advanced imaging technology called cryo-electron microscopy, holds promise for enhancing the understanding of how midnolin supports the survival of malignant cells in certain cancers, including leukemias, lymphomas, and multiple myelomas.
Their findings, published in the Proceedings of the National Academy of Sciences (PNAS), detail midnolin’s unique role in protein degradation, which diverges from classical cellular mechanisms.
According to Dr. Nagesh Peddada, an Assistant Professor at UT Southwestern, the structural insights into midnolin can influence the design of newer pharmaceuticals. These developments could potentially mitigate the severe side effects associated with current cancer therapies.
Dr. Peddada co-led the study along with Dr. Bruce Beutler, a prominent figure in immunology and a Nobel laureate in Physiology or Medicine. Dr. Beutler has effectively utilized mutagenesis in animal models to decode gene functions, contributing greatly to the field of genetics in host defense.
In their previous research, the Beutler Lab explored the effects of mutations in the Midn gene, which encodes the midnolin protein. They found that such mutations can shield mice that are genetically predisposed to B-cell leukemias and lymphomas. A notable point of their findings is that midnolin plays a pivotal role in B cells—an essential component of the adaptive immune system—that often undergo uncontrolled division in these malignancies.
When midnolin production was genetically suppressed in mice, the researchers observed a significant extension in the lifespans of the affected animals, effectively preventing the onset of these cancers.
The study revealed that midnolin assists B cells by transporting proteins to proteasomes—cellular structures responsible for degrading damaged or unnecessary proteins. Additionally, midnolin enhances proteasome activity, thus accelerating the elimination of defective proteins from cells.
A defining aspect of this mechanism is that proteins usually marked for destruction by proteasomes are tagged with ubiquitin. However, midnolin can facilitate the degradation of certain proteins without ubiquitin’s assistance. The specifics of this unique function had remained largely unclear until the recent structural analysis.
Using the Cryo-Electron Microscopy Facility at UT Southwestern, the team behind this study successfully captured three-dimensional images of midnolin bound to proteasomes with near-atomic resolution. These images disclosed critical regions of midnolin integral to its interaction with proteasomes, including a portion that mimics the shape of ubiquitin. This enable midnolin to unlock the pathway necessary for protein disposal.
Current treatment options for B-cell leukemias and lymphomas often include proteasome inhibitors, which, while effective, are associated with a host of side effects, including gastrointestinal disturbances, reduced platelet counts leading to bleeding risks, and neurotoxicity. Dr. Beutler suggests that targeting midnolin could offer a safer, more focused therapeutic approach, reducing the unwanted side effects commonly faced by patients undergoing current therapies. This represents a potential shift in treatment strategy, with future investigations planned by the Beutler Lab.
The research team also included other notable UTSW faculty members, such as Xiaochen Bai, Xue Zhong, Jin Huk Choi, Eva Maria Y. Moresco, Yan Yin, Danielle Renee Lazaro, Jianhui Wang, and Stephen Lyon, contributing their expertise to this important study.
Dr. Beutler, who serves as a Regental Professor, is honored with the Raymond and Ellen Willie Distinguished Chair in Cancer Research and is also a member of the Cellular Networks in Cancer Research Program at the Harold C. Simmons Comprehensive Cancer Center at UTSW.
This groundbreaking research was made possible through grants from the National Institutes of Health and The Welch Foundation, demonstrating the importance of collaborative efforts in advancing cancer treatment.
UT Southwestern Medical Center stands out as a top-tier academic medical center in the United States, integrating exceptional clinical care with cutting-edge biomedical research. With a faculty renowned for groundbreaking medical advances and a commitment to swiftly translating research into clinical practice, UT Southwestern remains dedicated to providing unparalleled healthcare across a multitude of specialties.
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