BMB Reports最新文献

The TP53 c.359A＞G mutation significantly disrupts the expression of the major TP53 transcript variant encoding p53 K120R by generating a new splice donor site. An antisense morpholino oligomer (AMO) targeting this mutation successfully restored normal splicing and the expression of the major TP53 variant. Given that p53 exerts its tumor suppressor function by regulating target genes responsible for growth arrest or apoptosis, the p53 K120R protein enhanced by AMO exhibits impaired transcriptional regulation of CDKN1A, a key growth arrest gene, while maintaining normal induction of the pro-apoptotic BBC3 gene. As a result, the mutant p53 K120R protein shows a defective cell growth arrest phenotype but retains apoptotic function, suggesting that it may still possess some tumor suppressor activity. Furthermore, lysine 120, known to provide a critical acetylation site for p53 activation, highlights the relevance of acetylation in tumor suppression through studies of the p53 K120R mutant. However, our findings demonstrate that targeting mutant TP53 mRNA with AMO is essential for restoring p53 function. In conclusion, this study emphasizes the potential of AMO-mediated splice correction as a therapeutic approach for TP53 mutations.

Mammalian ATG8 proteins (mATG8s) are essential for selective autophagy because they recruit various proteins with LC3- interacting region (LIR) motifs to autophagic membranes. The RavZ protein, secreted by Legionella pneumophila, and mammalian ATG4B possess functional LIR motifs that participate in lipidated mATG8 deconjugation on autophagic membranes. RavZ comprises three functional LIR motifs at the N- and Cterminal sides of its catalytic domain (CAD). This study demonstrated that LIR motifs at the N-terminal side of the CAD of RavZ are involved in autophagic membrane targeting and substrate recognition, while LIR motif at the C-terminal side facilitate autophagic membrane targeting. Our results also revealed that the C-terminal LIR motif in human ATG4B is pivotal in delipidating LC3B-phosphatidylethanolamine (PE), but it plays a minor role in pro-LC3B priming in the cytosol. Therefore, introducing a functional LIR motif to the N-terminal of ATG4B does not affect LC3B-PE delipidation. This study clearly described the position-dependent roles of LIR motifs in RavZ and ATG4B in cellular contexts.

Keratinocytes are susceptible to airborne particulate matter (PM) exposure, resulting in human skin barrier dysfunction. Therefore, it is important to find useful reagents to resolve skin damages caused by PM. Here, we explored the protective effect of 7S MaR1, a specialized pro-resolving mediator derived from docosahexaenoic acid, on skin inflammation and the oxidative stress induced by PM with a diameter 10 μm or less (PM₁₀) in human keratinocyte HaCaT cells. Interestingly, PM10-induced ROS generation was modulated by 7S MaR1 via the recovery of ROS scavenger genes. 7S MaR1 reduced PM₁₀-induced IL-6 expression via modulating the p38/ERK/NF-κB signaling pathways. These results demonstrate that PM₁₀ induces inflammatory cytokines, which can lead to skin diseases. In addition, 7S MaR1 can resolve inflammation caused by PM₁₀-induced oxidative stress and inflammatory cytokines.

Cereblon (CRBN) is an extensively expressed protein involved in crucial physiological processes. This study reveals CRBN's role in governing hepatic fibroblast growth factor 23 (FGF23) expression and production via the cyclic adenosine monophosphate (cAMP) pathway in diabetic conditions. The expression of hepatic Crbn, Yin Yang 1 (Yy1), and Fgf23 genes were significantly increased in diabetic mice and forskolin (FSK)-treated primary hepatocytes, correlating with elevated FGF23 production. Overexpression of Crbn and Yy1 increased hepatic FGF23 and cytokines by upregulating YY1 gene expression, which was reduced in Crbn- and Yy1-silenced mice and primary hepatocytes. Besides, we found that CRBN-mediated regulation of hepatic FGF23 involved YY1 recruitment to the Fgf23 gene promoters, evidenced by reporter assays, deletion studies, and mutant analyses. These findings identify CRBN and YY1 as key contributors to gluconeogenic signaling-driven FGF23 production and inflammation in diabetes, highlighting their potential as therapeutic targets for addressing metabolic disorders like diabetes.

The vascular system in plants facilitates long-distance transportation of water and nutrients through the xylem and phloem, while also providing mechanical support for vertical growth. Although many genes that regulate vascular development in rice have been identified, the mechanism by which epigenetic regulators control vascular development remains unclear. This study found that Rolled Fine Striped (RFS), a Chromodomain Helicase DNA-binding 3 (CHD3)/Mi-2 subfamily protein, regulates vascular development in rice by affecting the initiation and development of primordia. The rfs mutant was found to affect auxin-related genes, as revealed by RNA sequencing and reverse transcription-quantitative PCR analysis. The transcript levels of OsPIN1 and NAL1 genes were downregulated in rfs mutant, compared to the wild-type plant. The chromatin immunoprecipitation assays showed lower levels of H3K4me3 in the OsPIN1a and NAL1 genes in rfs mutant. Furthermore, exogenous auxin treatment partially rescued the reduced adventitious root vascular development in rfs mutant. Subsequently, exogenous treatments with auxin or an auxin-transport inhibitor revealed that the expression of OsPIN1a and NAL1 is mainly affected by auxin. These results provide strong evidence that RFS plays an important role in vascular development and root formation through the auxin signaling pathway in rice. [BMB Reports 2024; 57(10): 441-446].

Trained immunity, an innate immune response characterized by enhanced cellular responsiveness, exhibits a profound memory akin to adaptive immunity. This phenomenon involves intricate metabolic and epigenetic reprogramming triggered by stimuli such as β-glucan and BCG, shaping innate immune memory. Following elucidation of the background on trained immunity, it is important to explore its multifaceted roles in various pathological contexts. In this review, we delve into the specific contributions of trained immunity in the intricate landscape of viral infections, tumorigenesis, and diverse inflammatory diseases, shedding light on its potential as a therapeutic target, and offering comprehensive understanding of its broader immunological implications. [BMB Reports 2024; 57(10): 431-440].

Primary cilia are crucial for cellular balance, serving as sensors for external conditions. Nephronophthisis and related ciliopathies, which are hereditary and degenerative, stem from genetic mutations in cilia-related genes. However, the precise mechanisms of these conditions are still not fully understood. Our research demonstrates that downregulating PDIA6, leading to cilia removal, makes cells more sensitive to ferroptotic death caused by endoplasmic reticulum (ER) stress. The reduction of PDIA6 intensifies the ER stress response, while also impairing the regulation of primary cilia in various cell types. PDIA6 loss worsens ER stress, hastening ferroptotic death in proximal tubule epithelial cells, HK2 cells. Counteracting this ER stress can mitigate PDIA6 depletion effects, restoring both the number and length of cilia. Moreover, preventing ferroptosis corrects the disrupted primary ciliogenesis due to PDIA6 depletion in HK2 cells. Our findings emphasize the role of PDIA6 in primary ciliogenesis, and suggest its absence enhances ER stress and ferroptosis. These insights offer new therapeutic avenues for treating nephronophthisis and similar ciliopathies. [BMB Reports 2024; 57(10): 453-458].

The heterotrimeric molecular motor kinesin-2 is involved in the microtubule-dependent transport of intracellular cargo. It consists of two distinct motor subunits (KIF3A, and KIF3B) and a non-motor subunit, kinesin-associated protein 3 (KAP3). The cargo-binding domain (CBD) at the carboxyl (C)-terminus of KIF3s plays an important role in the interaction with several different binding proteins. To identify the binding proteins for heterotrimeric kinesin-2, we performed a yeast two-hybrid screen and found a new interaction with Disables-1 (Dab1), the intracellular adaptor protein of reelin receptors. Dab1 bound to the CBD of KIF3A, but did not interact with the C-terminal domain of KIF3B, KIF5B, KIF17 or KAP3. The phosphotyrosine binding (PTB) domain-containing region of Dab1 is essential for the interaction with KIF3A. KIF3A interacted with GST-Dab1, and GST-CaMKIIα, but did not interact with GST-apolipoprotein E receptor 2 (ApoER2)-C or with GST alone. When co-expressed in HEK-293T cells, Dab1 co-precipitated with KIF3A, but not with KIF5B. Dab1 and KIF3A were co-localized in cultured cells. We also identified deduced cell surface expression of ApoER2 in KIF3A dominant-negative cells. These results suggest that the KIF3A plays a role in the intracellular trafficking of ApoER2 to the cell surface. [BMB Reports 2024; 57(10): 447-452].

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer. HCC occurs people with chronic liver diseases. The purinergic receptor P2X 7 (P2RX7) is involved in tumor proliferation and growth. Also, P2RX7 is associated with tumor invasion and metastatic dissemination. High glucose utilization is important for the survival of various types of tumors. However, the role of P2RX7 in glucose metabolism and cellular survival of HCC remains unclear. Here, our results show that the gene and protein levels of P2RX7 were elevated in tumor cells of patients with HCC. The pharmacological inhibition of P2RX7 by A-804598, a selective P2RX7 antagonist, and genetic inhibition by P2RX7 knockdown suppressed the glycolytic activity by reduction of hexokinase 2 (HK2), a key enzyme of the glycolysis pathway, in human HCC cells. Also, both A-804598 treatment and P2RX7 knockdown induced cytotoxicity via inhibition of AKT activation which is critical for tumor cell survival in human HCC cells. Moreover, A-804598 treatment and P2RX7 knockdown increased cytotoxicity and caspase-3 activation in human HCC cells. These results suggest that inhibition of P2RX7 contributes to cytotoxicity by suppression of glycolysis and AKT activation in human HCC. [BMB Reports 2024; 57(10): 459-464].

Understanding estrogen receptor (ER) signaling pathways is crucial for uncovering the mechanisms behind estrogen-related diseases, such as breast cancer, and addressing the effects of environmental estrogenic disruptors. Traditionally, ER signaling involves genomic events, including ligand binding, receptor dimerization, and transcriptional modulation within cellular nuclei. However, recent research have revealed ERs also participate in non-genomic signaling pathways, adding complexity to their functions. Researchers use advanced fluorescence-based techniques, leveraging fluorescent probes (FPb) to study ER dynamics in living cells, such as spatial distribution, expression kinetics, and functional activities. This review systematically examines the application of fluorescent probes in ER signaling research, covering the visualization of ER, ligandreceptor interactions, receptor dimerization, estrogen response elements (EREs)-mediated transcriptional activation, and G-proteincoupled estrogen receptor (GPER) signaling. Our aim is to provide researchers with valuable insights for employing FPb in their explorations of ER signaling.