Exploring the Role of Ubiquitin-Proteasome System in the Pathogenesis of Parkinson's Disease.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder among the elderly population. The pathogenesis of PD encompasses genetic alterations, environmental factors, and age-related neurodegenerative processes. Numerous studies have demonstrated that aberrant functioning of the ubiquitin-proteasome system (UPS) plays a crucial role in the initiation and progression of PD. Notably, E3 ubiquitin ligases serve as pivotal components determining substrate specificity within UPS and are intimately associated with the regulation of various proteins implicated in PD pathology. This review comprehensively summarizes the mechanisms by which E3 ubiquitin ligases and deubiquitinating enzymes modulate PD-associated proteins and signaling pathways, while exploring the intricate relationship between UPS dysfunctions and PD etiology. Furthermore, this article discusses recent research advancements regarding inhibitors targeting PD-related E3 ubiquitin ligases.

NOLC1 was identified as a tumor suppressor gene in thyroid cancer and correlated with prognosis by bioinformatics.

Thyroid cancer (THCA) is the most common endocrine malignancy, mainly affecting women's unilateral glandular lobes. However, for relapsed and distant metastasis of THCA patients, the existing early diagnosis and treatment methods were still insufficient, and a new method was urgently needed to diagnose and treat them. Nucleolar and coiled-body phosphoprotein 1 (NOLC1) was one of the most phosphorylated proteins in the cell, which was located mainly in the nucleolus. In addition, more and more studies have confirmed that NOLC1 plays a crucial role in various pathological processes, such as the occurrence and progression of cancer and viral infection. A previous study showed that NOLC1, as a member of RNA-binding protein, was significantly correlated with the prognosis of THCA patients. However, further exploration of NOLC1 in THCA is limited. To further explore the role of NOLC1 in THCA, we conducted expression and survival prognosis analysis of NOLC1 using multiple databases. We also evaluated the correlation between NOLC1 gene expression and clinical characteristics of THCA patients. Furthermore, we analyzed the relationship between NOLC1 and other genes, followed by enrichment analysis to investigate its metabolic pathways and molecular metabolism processes. Additionally, we examined the association between immune cell infiltration in tumor microenvironment and NOLC1. Notably, through vitro experiments, we confirmed the tumor suppressive effect of NOLC1 on the proliferation and migration of human THCA cells, providing evidence for clinical diagnosis of THCA. Furthermore, we confirmed the tumor suppressive effect of NOLC1 in vivo xenograft assay. To sum up, our results suggest that NOLC1 is a tumor suppressor gene for THCA.

Regulation of apoptosis by ubiquitination in liver cancer.

Apoptosis is a programmed cell death process critical to cell development and tissue homeostasis in multicellular organisms. Defective apoptosis is a crucial step in the malignant transformation of cells, including hepatocellular carcinoma (HCC), where the apoptosis rate is higher than in normal liver tissues. Ubiquitination, a post-translational modification process, plays a precise role in regulating the formation and function of different death-signaling complexes, including those involved in apoptosis. Aberrant expression of E3 ubiquitin ligases (E3s) in liver cancer (LC), such as cellular inhibitors of apoptosis proteins (cIAPs), X chromosome-linked IAP (XIAP), and linear ubiquitin chain assembly complex (LUBAC), can contribute to HCC development by promoting cell survival and inhibiting apoptosis. Therefore, the review introduces the main apoptosis pathways and the regulation of proteins in these pathways by E3s and deubiquitinating enzymes (DUBs). It summarizes the abnormal expression of these regulators in HCC and their effects on cancer inhibition or promotion. Understanding the role of ubiquitination in apoptosis and LC can provide insights into potential targets for therapeutic intervention.

Roles of NOLC1 in cancers and viral infection.

BACKGROUND: The nucleolus is considered the center of metabolic control and an important organelle for the biogenesis of ribosomal RNA (rRNA). Nucleolar and coiled-body phosphoprotein 1(NOLC1), which was originally identified as a nuclear localization signal-binding protein is a nucleolar protein responsible for nucleolus construction and rRNA synthesis, as well as chaperone shuttling between the nucleolus and cytoplasm. NOLC1 plays an important role in a variety of cellular life activities, including ribosome biosynthesis, DNA replication, transcription regulation, RNA processing, cell cycle regulation, apoptosis, and cell regeneration. PURPOSE: In this review, we introduce the structure and function of NOLC1. Then we elaborate its upstream post-translational modification and downstream regulation. Meanwhile, we describe its role in cancer development and viral infection which provide a direction for future clinical applications. METHODS: The relevant literatures from PubMed have been reviewed for this article. CONCLUSION: NOLC1 plays an important role in the progression of multiple cancers and viral infection. In-depth study of NOLC1 provides a new perspective for accurate diagnosis of patients and selection of therapeutic targets.

The E3 Ligases in Cervical Cancer and Endometrial Cancer.

Endometrial (EC) and cervical (CC) cancers are the most prevalent malignancies of the female reproductive system. There is a global trend towards increasing incidence and mortality, with a decreasing age trend. E3 ligases label substrates with ubiquitin to regulate their activity and stability and are involved in various cellular functions. Studies have confirmed abnormal expression or mutations of E3 ligases in EC and CC, indicating their vital roles in the occurrence and progression of EC and CC. This paper provides an overview of the E3 ligases implicated in EC and CC and discusses their underlying mechanism. In addition, this review provides research advances in the target of ubiquitination processes in EC and CC.

The functions and effects of CUL3-E3 ligases mediated non-degradative ubiquitination.

Ubiquitination of substrates usually have two fates: one is degraded by 26S proteasome, and the other is non-degradative ubiquitination modification which is associated with cell cycle regulation, chromosome inactivation, protein transportation, tumorigenesis, achondroplasia, and neurological diseases. Cullin3 (CUL3), a scaffold protein, binding with the Bric-a-Brac-Tramtrack-Broad-complex (BTB) domain of substrates recognition adaptor and RING-finger protein 1 (RBX1) form ubiquitin ligases (E3). Based on the current researches, this review has summarized the functions and effects of CUL3-E3 ligases mediated non-degradative ubiquitination.