Nuclear pore complexes (NPCs) are made up of various proteins that act as channels to transport molecules into and out of the nucleus. They play a crucial role in regulating important cellular functions including gene expression, chromatin organization, and RNA processes that impact cell survival, growth, and specialization.
Recent studies, including research by Maximiliano D’Angelo, Ph.D., from Sanford Burnham Prebys’ Cancer Metabolism and Microenvironment Program, have found differences in NPCs in cancer cells. However, the impact of these changes on tumor development and malignancy, as well as the normal function of NPCs in regular cells, is not well understood.
In a new article published on June 5, 2024, in Science Advances, D’Angelo, along with Valeria Guglielmi, Ph.D., and Davina Lam, identify Nup358, one of about 30 proteins that make up the NPCs, as playing a role in the early stages of myeloid malignancies.peripheral tissues, released into the bloodstream, and then migrate back to the bone marrow to further mature into various types of blood cells. We found that in the absence of Nup358, these early progenitor cells are not released into the bloodstream as efficiently, leading to a decrease in mature myeloid cells.”
Furthermore, the researchers discovered that Nup358 deficiency led to the activation of a specific cellular stress response pathway known as the unfolded protein response, or UPR. “This stress response is normally activated in cells when there is an accumulation of misfolded proteins,” explained D’Angelo. “We found that Nup358-deficient cells have an increase in misfolded proteins, which in turn activates the UPR. This pathway can ultimately lead to cell death, and we believe it may contribute to the loss of mature myeloid cells in our mouse model.”
the study provides new insights into the role of Nup358 in the regulation of myeloid cell production and maturation, and may have implications for the development of therapies for myeloid disorders, including leukemias. “Our findings suggest that targeting Nup358 or the pathways it regulates could be a potential strategy for modulating myeloid cell production in the context of disease,” said D’Angelo. “We are excited to further explore these possibilities in future research.”
The hematopoietic stem cells in the bone marrow differentiate to create various types of blood cells.
According to Gugliemi, there are different groups of MPPs responsible for producing specific blood cells. Without Nup358, the MPPs that produce myeloid cells, such as red blood cells and components of the immune system, have difficulty progressing through the differentiation process.
Essentially, Nup358 plays a crucial role in the early stages of myelopoiesis, or the production of myeloid cells. This discovery is significant as it provides insights into the development of blood cells.
The study aimed to understand the role of Nup358 in blood malignancies.
The results are part of D’Angelo’s ongoing research into the functions of NPCs in healthy cells and their connection to immune system problems and cancer development.
D’Angelo’s ultimate objective is to create new treatments that target transport machinery like NPCs. He recently obtained a Discovery Grant of $300,000 from the American Cancer Society to further his research.
This study was partially supported by a Research Scholar Grant from the American Cancer Society.