Molecular And Cellular Biology[JOURNAL]
Sun
200 papers
Net1 Controls Src Activation to Regulate Breast Cancer Cell Motility and Invasion.
Zuo Y, Carr HS, Li W … +2 more , Zhang S, Frost JA
Mol Cell Biol · 2025 · PMID 40765140 · Publisher ↗
The cytoplasmic tyrosine kinase Src supports many phenotypes in cancer cells, including proliferation, migration and invasion, survival, and metastasis. We have previously shown that Src promotes cytoplasmic localization...
The cytoplasmic tyrosine kinase Src supports many phenotypes in cancer cells, including proliferation, migration and invasion, survival, and metastasis. We have previously shown that Src promotes cytoplasmic localization of the RhoGEF Net1, where it stimulates RhoA activation, breast cancer cell motility, and extracellular matrix invasion. In the present work, we show that the Net1 expression in human breast tumors correlates with Src phosphorylation on its activating site Y419. We also show in human breast cancer cell lines that endogenous Net1 and Src interact, and that Net1 expression is required for full Src activation. Net1 must localize to the cytosol to promote Src activation, but surprisingly, the catalytic activity of Net1 toward Rho GTPases is not necessary for Src activation. Instead, Net1 requires interaction with the scaffolding protein Dlg1. Dlg1 knockdown prevents Src activation by Net1 and precludes interaction between Net1 and Src. Moreover, Net1 knockdown cooperates with small molecule inhibition of Src to inhibit breast cancer cell motility and extracellular matrix invasion. These data show a previously unrecognized relationship between Net1 and Src in human breast tumors and breast cancer cell lines, and suggest that therapeutic targeting of Net1 may be of benefit in breast cancers with elevated Src activity.
A Mutation in the RNA-Binding Protein Cth2 Limits the Adaptation of a Subset of Wild Yeast Strains to Iron Deficiency.
Valera-García E, Sorribes-Dauden R, Puig S
Mol Cell Biol · 2025 · PMID 40757737 · Publisher ↗
Iron is an essential micronutrient for eukaryotic organisms. In response to iron deficiency, the yeast optimizes iron utilization by downregulating nonessential iron-dependent processes, such as mitochondrial respiratio...
Iron is an essential micronutrient for eukaryotic organisms. In response to iron deficiency, the yeast optimizes iron utilization by downregulating nonessential iron-dependent processes, such as mitochondrial respiration. This regulatory mechanism is mediated by a mRNA-binding protein designated Cth2. In response to iron scarcity, Cth2 binds through its tandem zinc-finger (TFZ) domain to multiple mRNAs encoding proteins that are necessary for iron-dependent pathways. This binding limits the expression of these mRNAs by promoting their degradation and inhibiting their translation. In this study, we have examined a set of wild yeast strains that share a G195R mutation within the Cth2 TZF domain. By genetically editing both laboratory and wild yeast strains, we demonstrate that the Cth2-G195R protein is defective in binding and degradation of its target transcripts, and it accumulates in the nucleus of the cell, leading to a significant growth defect in iron-deficient conditions. Some of these wild yeast strains also display enhanced tolerance to high iron conditions, indicating that they have adapted to environments with elevated iron levels and have consequently diminished their capacity to grow in iron-limiting conditions. These findings highlight the crucial function of Cth2 in enabling yeast cells to adapt to iron-deficient environments.
Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.
Saleiro D, Wen JQ, Zannikou M … +22 more , Lee B, Kosciuczuk EM, Nehlsen SD, Munshi A, Chen X, Oku CV, Hryhorysak B, Guillen Magaña JN, Heneche J, Fischietti M, Ilut L, Small SH, Cotton A, Hall T, Payton MA, Beauchamp EM, Yue F, Kocherginsky M, Bartom ET, Hoffman R, Crispino JD, Platanias LC
Mol Cell Biol · 2025 · PMID 40697155 · Full text
Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment a...
Defining the mechanisms that promote development and progression of myeloproliferative neoplasms (MPNs) is important for understanding the mechanisms of malignant hematopoiesis and critical development of new treatment approaches. We provide evidence for a key and essential role of the kinase ULK1 in MPN pathophysiology. Our studies demonstrate that genetic or pharmacological targeting of ULK1 delays substantially disease development in -mutant MPN models in vivo and establish that ULK1 activity is required for transcription of genes that control hematopoietic stem cell differentiation. Pharmacological targeting of ULK1 exhibits potent therapeutic effects, resulting in reduction of early stage erythroid progenitors in spleen and bone marrow, decreased levels of hemoglobin, and reduced spleen size in MPN mouse models in vivo. Taken together, these findings provide the first evidence for a novel protumorigenic role for ULK1 downstream of the hyperactive JAK2 signaling in MPNs and raise the potential of ULK1 as a new therapeutic target for the treatment of MPNs.
Molecular Function of Midnolin and Its Relevance to Parkinson's Disease.
Obara Y, Chiba A
Mol Cell Biol · 2025 · PMID 40693841 · Publisher ↗
Midnolin () was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MID...
Midnolin () was originally discovered as a gene expressed specifically in the mouse midbrain at the embryonic developmental stage; MIDN was localized in the nucleus/nucleolus. Although the pathophysiological roles of MIDN remained largely unknown for many years after its discovery, its molecular functions and relevance to diseases have gradually become clearer. In PC12 cells, a rat neuronal model cell line, liquidity factors that are necessary for neurite outgrowth are reported to induce gene expression. In addition, MIDN is required for E3 ubiquitin-protein ligase parkin expression, suggesting that MIDN is important for the development and maintenance of neuronal functions. Notably, it was recently reported that MIDN plays fundamental roles in the ubiquitin-independent proteasomal degradation of various nuclear proteins and transcription factors. Regarding the relationship between MIDN and diseases, copy number loss of is associated with Parkinson's disease, suggesting that is a genetic risk factor for this disease. In addition, MIDN is relevant to many types of malignant cancer, including B-cell lymphoma and liver cancer. Thus, MIDN is an essential molecule for the maintenance of homeostasis, and its functional disorder triggers multiple diseases depending on the affected tissues/organs. therefore shows promise as a potential therapeutic target and prognostic biomarker.
miR-365-3p Regulates Gastrointestinal Dysfunction in Diabetes Mellitus Rats via the TLR4/MyD88/NF-κB Pathway.
Xiao J, Gao B, Xiao Y … +1 more , Liu X
Mol Cell Biol · 2025 · PMID 40693422 · Publisher ↗
Over half of diabetes mellitus (DM) patients suffer from gastrointestinal motility disorders. miR-365-3p is involved in DM progression, but its role in gastrointestinal motility disorders remains unclear. This study expl...
Over half of diabetes mellitus (DM) patients suffer from gastrointestinal motility disorders. miR-365-3p is involved in DM progression, but its role in gastrointestinal motility disorders remains unclear. This study explored whether miR-365-3p affects gastrointestinal motility in diabetic rats via the TLR4/MyD88/NF-κB pathway. A DM rat model was established using a high-fat, high-sugar diet and injected with a miR-365-3p mimic/inhibitor. DM symptoms, gastric emptying, intestinal propulsion rates, and gastrointestinal transit time were assessed. HE and TUNEL staining evaluated gastrointestinal pathology and apoptosis. qRT-PCR detected miR-365-3p levels, while ELISA assessed gastrointestinal motility-related factors. Immunofluorescence and Western blot analyzed C-kit, TLR4, and pathway proteins. DM rats exhibited increased body weight, blood glucose, and glucose intolerance, with reduced fasting insulin, confirming successful modeling. miR-365-3p was downregulated in DM rats. Injection of miR-365-3p mimic alleviated DM symptoms, reduced gastrointestinal tissue damage and apoptosis, and improved motility. The TLR4 agonist CRX-527 impaired these effects. In conclusion, miR-365-3p overexpression alleviates DM symptoms, gastrointestinal injury, and motility disorders by inhibiting the TLR4/MyD88/NF-κB pathway, offering a potential therapeutic target.
The Ubiquitin E3 Ligase UBE3A Regulates GRIPAP1 and PACSIN1 Proteins Linked to the Endocytic Recycling of AMPA Receptors.
Drebushenko L, Belous N, Lischka FW … +5 more , Zhou Q, Malci A, Sidorov MS, Burnett B, Doughty ML
Mol Cell Biol · 2025 · PMID 40671377 · Publisher ↗
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the ne...
Angelman syndrome (AS) is a neurodevelopmental disorder characterized by cognitive and language impairments, seizures, reduced or fragmented sleep, motor ataxia, and a characteristic happy affect. AS arises due to the neuronal loss of UBE3A, an E3 ligase that regulates protein abundance through the addition of lysine 48 (K48)-linked polyubiquitin chains to proteins targeted for degradation by the ubiquitin proteasome system (UPS). Using a dual SMAD inhibition protocol to derive cortical neurons from human induced pluripotent stem cells, we examined deletion effects on the neuronal proteome by liquid chromatography tandem mass spectrometry (LC-MS/MS). LC-MS/MS identified 645 proteins differentially abundant between knockout (KO) and isogenic wild-type control cortical neurons. Proteins with increased abundance with UBE3A loss of function include GRIPAP1 and PACSIN1, synaptic proteins implicated in AMPA receptor recycling. We provide evidence UBE3A polyubiquitinates PACSIN1 and GRIPAP1 to regulate protein turnover, with potential implications for impaired activity-dependent synaptic plasticity observed in AS.
MARBP-lncRNA Complexes Alter Gene Function Through Modulation of Epigenetic Landscape.
Maji N, Dutta A, Anand A … +2 more , Chatterjee S, Chattopadhyay S
Mol Cell Biol · 2025 · PMID 40605795 · Publisher ↗
Chromatin structure in eukaryotes is organized into functional domains through protein-DNA complexes. The -acting DNA elements are attached to the nuclear matrix, known as scaffold/matrix attachment regions (S/MARs). The...
Chromatin structure in eukaryotes is organized into functional domains through protein-DNA complexes. The -acting DNA elements are attached to the nuclear matrix, known as scaffold/matrix attachment regions (S/MARs). The associated protein partners known as matrix-associated region binding proteins (MARBPs). The coordinated interactions between MARBP and MARs to the nuclear scaffold act as an anchor for chromatin attachment and influences the regulation of gene expression. MARBPs modulate local epigenetic landscape of chromatin through the epigenetic modifiers. This function is executed by participating in the posttranslational modifications (PTMs) of DNA and histones. Such epigenetic changes are governed by crosstalk between long noncoding RNAs (lncRNAs) and associated MARBPs. Thus, dysregulation of either MARBPs or lncRNAs may alter gene expression potentially contributing to various disease manifestations. In this review, we elaborate on regulatory crosstalk between lncRNAs and MARBPs, its implication in human diseases, and possible therapeutics.
Hypoxia Signaling in the Cell Type-Specific Regulation of Erythropoietin Production Throughout Mammalian Development.
Suzuki N, Nakai T, Iwamura Y … +1 more , Kato K
Mol Cell Biol · 2025 · PMID 40574673 · Publisher ↗
To maintain the oxygen supply to peripheral organs, the production of erythropoietin (EPO), an essential growth factor for red blood cells, is controlled in a hypoxia-inducible manner in mammals. The developmentally earl...
To maintain the oxygen supply to peripheral organs, the production of erythropoietin (EPO), an essential growth factor for red blood cells, is controlled in a hypoxia-inducible manner in mammals. The developmentally earliest site of EPO production, which is necessary for primitive erythropoiesis in the yolk sac and bloodstream, is found in a subset of neural crest and neuroepithelial cells during mid-stage embryonic development. These neural EPO-producing (NEP) cells maintain their immaturity and EPO-producing ability in their hypoxic microenvironment, which is inherent in developing embryos. After oxygenation of the fetus by the establishment of the circulatory system and EPO-driven erythropoiesis, the site of EPO production shifts to hepatocytes of the fetal liver, where erythropoiesis also occurs. In adult mammals, a specific fibroblastic cell fraction in the renal interstitium, known as renal EPO-producing (REP) cells, secretes the majority of EPO to support bone marrow erythropoiesis. Hypoxia-inducible transcription factors (HIFs) are involved in EPO production across NEP cells, hepatocytes, and REP cells, whereas the regulatory mechanisms are distinct for each cell type. This review summarizes the molecular mechanisms of gene regulation throughout all life stages and discusses the associations of HIF signaling in EPO production with other stimuli, including inflammation and metabolism.
Differential Transcriptional Activity of ΔNp63β Is Encoded by an Isoform-Specific C-Terminus.
McCann AA, Sammons MA
Mol Cell Biol · 2025 · PMID 40545896 · Full text
p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the prog...
p63 is a clinically relevant transcription factor heavily involved in development and disease. Mutations in the p63 DNA-binding domain cause severe developmental defects and overexpression of p63 plays a role in the progression of epithelial-associated cancers. Unraveling the specific biochemical mechanisms underlying these phenotypes is made challenging by the presence of multiple p63 isoforms and their shared and unique contributions to development and disease. Here, we explore the function of the p63 isoforms ΔNp63ɑ and ΔNp63β to determine the contribution of C-terminal splice variants on known and unique molecular and biochemical activities. Using RNA-seq and ChIP-seq on isoform-specific cell lines, we show that ΔNp63β regulates both canonical ΔNp63ɑ targets and a unique set of genes with varying biological functions. We demonstrate that most genomic binding sites are shared, however the enhancer-associated histone modification H3K27ac is highly enriched at ΔNp63β binding sites relative to ΔNp63ɑ. An array of ΔNp63β C-terminal mutants demonstrates the importance of isoform-specific C-terminal domains in regulating these unique activities. Our results provide novel insight into differential activities of p63 C-terminal isoforms and suggest future directions for dissecting the functional relevance of these and other transcription factor isoforms in development and disease.
Nuclear Roles for Canonically Lysosomal Proteases.
Enneking AE, Khorey MM, Edgington-Mitchell LE
Mol Cell Biol · 2025 · PMID 40544346 · Publisher ↗
While the cysteine proteases legumain and cathepsins have traditionally been known as "lysosomal" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes,...
While the cysteine proteases legumain and cathepsins have traditionally been known as "lysosomal" proteases, there is increasing evidence to suggest that they also contribute to a wide range of extralysosomal processes, including in the nucleus. This review aims to provide a comprehensive overview of the current knowledge regarding the translocation of these proteases to the nucleus and their functions on arrival. We discuss possible mechanisms for transporting these proteases to the nucleus, including the presence of a nuclear localization signal sequence or hitchhiking on other proteins that possess this sequence. This transport requires the proteases to first reach the cytosol, which may occur via direct cytosolic translation of truncated proteases or downstream of lysosomal membrane permeabilization. We also discuss the evidence for functions of these proteases upon arrival to the nucleus, including cell cycle progression, cell differentiation, cell death, immune regulation, and epigenetic regulation. As protease substrate profiling methods continue to improve, it is anticipated that many new nuclear substrates and interacting partners will be identified to reveal additional functions for nuclear proteases.
Identification of a Novel Intracellular Function of the Secreted Ribonuclease RNASE1 in Inhibiting Gene Expression.
Singh R, Archibald A, Li XL … +8 more , Kumar R, Das S, Pehrsson EC, Zhao PX, Wen X, Chari R, Grammatikakis I, Lal A
Mol Cell Biol · 2025 · PMID 40525876 · Full text
RNASE1 is a ribonuclease secreted by cells and degrades extracellular RNAs. Here, we unexpectedly found that RNASE1, in addition to being secreted, is predominantly localized to the nucleus and functions to inhibit gene...
RNASE1 is a ribonuclease secreted by cells and degrades extracellular RNAs. Here, we unexpectedly found that RNASE1, in addition to being secreted, is predominantly localized to the nucleus and functions to inhibit gene expression in human colorectal cancer (CRC) cells. expression is highly cell type-specific and is restricted to well-differentiated CRC cells where its transcription is activated by the pioneer transcription factor FOXA1. Using CRISPR interference utilizing three independent sgRNAs targeting the locus followed by RNA-seq, we found that upon depletion of RNASE1, most of the differentially expressed RNAs are modestly but significantly upregulated suggesting that RNASE1 predominantly functions to inhibit gene expression. In CRC patients, is significantly downregulated and high expression is associated with better patient survival, indicating a potential tumor suppressive function. Consistent with this, RNASE1 depletion results in increased proliferation and clonogenicity indicating that RNASE1 inhibits the growth of CRC cells. Finally, a promising RNASE1 target among the most significantly upregulated mRNAs upon RNASE1 depletion is (Dickkopf inhibitor 1) which is upregulated in CRC and negatively regulated by RNASE1. Collectively, this initial characterization of endogenous RNASE1 uncovers a function of RNASE1 in inhibition of gene expression and CRC cell proliferation.
Understanding the Impact of Mutations in the Cystathionine Beta-Synthase Gene: Towards Novel Therapeutics for Homocystinuria.
Majtan T, Mijatovic E, Petrosino M
Mol Cell Biol · 2025 · PMID 40495464 · Publisher ↗
Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders,...
Protein misfolding and conformational instability drive protein conformational disorders, causing either accelerated degradation and loss-of-function, as in inherited metabolic disorders like lysosomal storage disorders, or toxic aggregation and gain-of-function, as in neurodegenerative diseases like Alzheimer's disease or amyotrophic lateral sclerosis. Classical homocystinuria (HCU), an inborn error of sulfur amino acid metabolism, results from cystathionine beta-synthase (CBS) deficiency. CBS regulates methionine conversion into metabolites critical for redox balance (cysteine, glutathione) and signaling (HS). Pathogenic missense mutations in the CBS gene often impair folding, cofactor binding, stability or oligomerization rather than targeting the key catalytic residues of the CBS enzyme. Advances in understanding of CBS folding and assembly as well as CBS interactions with cellular proteostasis network offer potential for therapies using pharmacological chaperones (PCs), i.e., compounds facilitating proper folding, assembly or cellular trafficking. This review discusses progress in identifying PCs for HCU, including chemical chaperones, cofactors, and proteasome inhibitors. We outline future directions, focusing on high-throughput screening and structure-based drug design to develop CBS-specific PCs. These could stabilize mutant CBS, enhance its stability and restore activity, providing new treatments for HCU and possibly other conditions related to dysregulated CBS, such as cancer or Down's syndrome.
HEB Restrains Effector Gene Expression during Early CD8 Memory Precursor T Cell Differentiation.
Leung JP, Haddadi S, Geuenich MJ … +6 more , Tuncer A, Musiime V, Wang C, Zúñiga-Pflücker JC, Campbell KR, Anderson MK
Mol Cell Biol · 2025 · PMID 40418130 · Full text
Memory T cells are essential for maintaining long-term adaptive immunity. Memory cell precursors and short-lived effector cells emerge from undifferentiated naïve T cells directly downstream of TCR signaling but little i...
Memory T cells are essential for maintaining long-term adaptive immunity. Memory cell precursors and short-lived effector cells emerge from undifferentiated naïve T cells directly downstream of TCR signaling but little is known about how this lineage choice is regulated at the molecular level. The transcription factor HEB is known to be an important regulator of thymic T cell development, but how it functions in peripheral T cell differentiation is poorly understood. We assessed the role of HEB in the differentiation of memory-like T cell precursors by inducing TCR signaling in CD8 T cells in the context of memory-polarizing cytokines or inflammatory conditions and found that CD8 T cells from HEB-deficient mice underwent accelerated differentiation as compared to WT cells. Transcriptomic analysis revealed aberrant upregulation of immune response genes and decreased expression of genes promoting stemness from the earliest stages of post-TCR signal activation and persisting throughout the course of differentiation. In addition, acute viral infection of HEB cKO mice resulted in enhanced memory precursor cell formation and increased effector functionality. Therefore, we have identified HEB as a central participant in the gene regulatory networks that regulate early CD8 memory T cell differentiation and effector gene expression. This study showed that naïve CD8 T cells lacking HEB exhibit increased TCR signal strength and loss of signatures of stem-ness, revealing a role for HEB in promoting immune memory.
Liver Receptor Homolog-1 Deficiency Impairs Alcohol-Associated Liver Disease Owing to Decrease of Aldehyde Dehydrogenase 1 Family Member B1 Gene Expression.
Seo MH, Lee JH, Lee EH … +5 more , Mukherjee S, Park SY, Bae JH, Song DK, Im SS
Mol Cell Biol · 2025 · PMID 40415444 · Publisher ↗
Ethanol is detoxified in the liver, and its intake causes hepatic lipid accumulation. The liver receptor homolog-1 (LRH-1) regulates lipid and bile acid metabolism, but its role in ethanol metabolism remains unclear. Thi...
Ethanol is detoxified in the liver, and its intake causes hepatic lipid accumulation. The liver receptor homolog-1 (LRH-1) regulates lipid and bile acid metabolism, but its role in ethanol metabolism remains unclear. This study aimed to explore the relationship between ethanol-induced lipid accumulation and LRH-1. To investigate the role of LRH-1 in hepatic ethanol metabolism, LRH-1 and liver-specific LRH-1 mice were fed a Lieber-DeCarli diet for 3 weeks. The results showed that ethanol-fed LRH-1 mice exhibited increased neutral fat, total cholesterol, liver damage markers, and acetaldehyde levels. Moreover, ethanol-fed LRH-1 mice displayed decreased fatty acid oxidation, impaired mitochondrial function, and increased reactive oxygen species levels. To identify LRH-1 targets in ethanol metabolism, RNA sequencing analysis revealed significant changes in genes involved in fatty acid metabolism between the control and ethanol groups. Notably, in the absence of LRH-1, ethanol metabolism genes showed a reduction in aldehyde dehydrogenase 1 family member b1 (ALDH1B1) expression. Furthermore, LRH-1 overexpression in HepG2 cells led to increased ALDH1B1 expression, and ChIP sequencing data confirmed the LRH-1 binding peaks in the ALDH1B1 promoter region. In conclusion, this study confirms that LRH-1 depletion results in decreased ALDH1B1 expression, leading to acetaldehyde accumulation and accelerated intrahepatic fat accumulation.
An Intrinsically Disordered Region of the FACT Subunit, Spt16, Promotes Chromatin Disassembly in Stimulating the Pre-Initiation Complex Formation at the Promoter for Transcription Initiation .
Barman P, Bhaumik SR
Mol Cell Biol · 2025 · PMID 40405832 · Publisher ↗
Previous structural and biochemical studies revealed that a negatively charged intrinsically disordered region (IDR) at the C-terminal of the Spt16 subunit of an evolutionarily conserved heterodimeric histone chaperone,...
Previous structural and biochemical studies revealed that a negatively charged intrinsically disordered region (IDR) at the C-terminal of the Spt16 subunit of an evolutionarily conserved heterodimeric histone chaperone, FACT (cilitates hromatin ranscription), interacts with histone H2A-H2B dimer, and hence interferes the interaction of DNA with histone H2A-H2B dimer. However, the functional relevance of the binding of Spt16's IDR to histone H2A-H2B dimer with impact on chromatin dynamics and transcription has not been clearly elucidated in living cells. Here, we show that Spt16's IDR facilitates the eviction of histone H2A-H2B dimer (and hence chromatin disassembly) from the inducible promoters upon transcription induction. Such facilitation of chromatin disassembly by Spt16's IDR stimulates the pre-initiation complex (PIC) formation at the promoter, and hence transcription initiation. Further, we find that Spt16's IDR regulates chromatin reassembly at the coding sequence in the wake of elongating RNA polymerase II. Collectively, our results reveal that Spt16's IDR facilitates promoter chromatin disassembly for stimulation of the PIC formation for transcription initiation with additional function in chromatin reassembly at the coding sequence in the wake of elongating RNA polymerase II, thus illuminating novel IDR regulation of chromatin dynamics and transcription .
ALYREF Promotes Progression of Intrahepatic Cholangiocarcinoma through Increasing the Level of Isocitrate Dehydrogenase 1 in an m5C-Dependent Manner.
Hao Z, Yang H, Zhu W … +3 more , Yu D, Cao Y, Wu Y
Mol Cell Biol · 2025 · PMID 40369958 · Publisher ↗
RNA 5-methylcytosine (m5C) modification has emerged as an important regulatory mechanism in the progression of human cancers, including hepatobiliary tumors. The m5C "reader" Aly/REF export factor (ALYREF) was recently f...
RNA 5-methylcytosine (m5C) modification has emerged as an important regulatory mechanism in the progression of human cancers, including hepatobiliary tumors. The m5C "reader" Aly/REF export factor (ALYREF) was recently found to be identified as a prognostic biomarker in liver cancer. However, its exact role in intrahepatic cholangiocarcinoma (ICC) progression is unclear. In this study, ALYREF was found to be upregulated in ICC tissues and cells. The gain- and loss-of-function experiments indicated that ALYREF promoted cell proliferation and invasion and suppressed cell apoptosis. Moreover, we found that isocitrate dehydrogenase 1 (IDH1), a metastatic marker of liver cancer, was also upregulated in ICC tissues, displayed a relatively strong positive correlation with the level of ALYREF, and was positively regulated by ALYREF. As an m5C "reader", ALYREF interacted with m5C-IDH1 mRNA and increased its stability. ALYREF knockdown partially eliminated the promotion of IDH1 on ICC cell proliferation and invasion. ALYREF positively regulated NRF2-driven glutathione synthesis in ICC cells, which was reversed by IDH1 silencing. Finally, in a xenograft tumor mouse model, knockdown of ALYREF or treatment with ivosidenib (an IDH1 inhibitor) significantly suppressed tumor growth in vivo. In conclusion, ALYREF promotes ICC progression by increasing IDH1 levels in an m5C-dependent manner.
Elevated Type I Interferon Signaling Defines the Proliferative Advantage of ARF and p53 Mutant Tumor Cells.
Mabry A, Kuzmicki CE, O'Brien A … +2 more , Maggi LB, Weber JD
Mol Cell Biol · 2025 · PMID 40351125 · Full text
The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massiv...
The tumor suppressors p53 and ARF collaborate to prevent unwarranted cell proliferation and as such are two of the most frequently mutated genes in human cancer. Concomitant loss of functional p53 and ARF leads to massive gains in cell proliferation and transformation and is often observed in some of the most aggressive human cancer subtypes. These phenotypic gains are preceded by increased type I interferon (IFN) signaling that involves canonical STAT1 activation and a subsequent IFN-stimulated gene (ISG) signature. Here, we show that cells lacking p53 and ARF require active JAK1 to phosphorylate STAT1 on Y701 to maintain their high rate of proliferation. In fact, the use of selective JAK1 inhibitors ruxolitinib or baricitinib inhibited the induction of ISG's and the proliferation of p53 and ARF deleted cells. We identify a group of solid human tumors that lack functional p53 and ARF, show an expression signature of the upregulated type I IFN response genes, and are sensitive to selective JAK1 inhibitors. These data suggest that the type I IFN response acts as a positive driver of proliferation in the absence of p53 and ARF and, as such, presents itself as a potential therapeutic target in aggressive solid tumors.
Key Mechanisms in Lysosome Stability, Degradation and Repair.
Zhang R, Vooijs MA, Keulers TG
Mol Cell Biol · 2025 · PMID 40340648 · Full text
Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity an...
Lysosomes are organelles that play pivotal roles in macromolecule digestion, signal transduction, autophagy, and cellular homeostasis. Lysosome instability, including the inhibition of lysosomal intracellular activity and the leakage of their contents, is associated with various pathologies, including cancer, neurodegenerative diseases, inflammatory diseases and infections. These lysosomal-related pathologies highlight the significance of factors contributing to lysosomal dysfunction. The vulnerability of the lysosomal membrane and its components to internal and external stimuli make lysosomes particularly susceptible to damage. Cells are equipped with mechanisms to repair or degrade damaged lysosomes to prevent cell death. Understanding the factors influencing lysosome stabilization and damage repair is essential for developing effective therapeutic interventions for diseases. This review explores the factors affecting lysosome acidification, membrane integrity, and functional homeostasis and examines the underlying mechanisms of lysosomal damage repair. In addition, we summarize how various risk factors impact lysosomal activity and cell fate.
Protein Phosphatase 1 Regulatory Subunit PNUTS Prevents CENP-A Mislocalization and Chromosomal Instability.
Balachandra V, Thomas M, Shrestha RL … +7 more , Sethi SC, Chari R, Lin S, Chih-Chien Cheng K, Karpova TS, Caplen NJ, Basrai MA
Mol Cell Biol · 2025 · PMID 40270285 · Full text
Chromosomal instability (CIN), a major hallmark of cancer, can be driven by defects in the integrity of centromere or kinetochore structure. Coordinated control of phosphorylation and dephosphorylation activities during...
Chromosomal instability (CIN), a major hallmark of cancer, can be driven by defects in the integrity of centromere or kinetochore structure. Coordinated control of phosphorylation and dephosphorylation activities during cell division is critical to ensure chromosomal stability. Overexpression of the centromeric histone H3 variant CENP-A is observed in many cancers, and its mislocalization to noncentromeric regions promotes CIN. We identified protein phosphatase 1 (PP1) nuclear targeting subunit (PNUTS) as a top candidate in a genome-wide siRNA screen for gene depletions that lead to increased nuclear CENP-A levels. Here, we define a role for PNUTS in preventing CENP-A mislocalization and CIN. Depletion of PNUTS resulted in high nuclear CENP-A levels throughout the cell cycle in a PP1-dependent manner. Consistent with these results, mislocalization of CENP-A and its interacting partner CENP-C were observed on mitotic chromosomes from PNUTS-depleted cells. Defects in kinetochore integrity and CIN phenotypes were also observed in PNUTS-depleted cells. Mechanistically, we show that depletion of the histone H3.3 chaperone DAXX suppresses the mislocalization of CENP-A and micronuclei incidence in PNUTS-depleted cells. In summary, our studies highlight the importance of phospho-regulation mediated by PNUTS in preventing CENP-A mislocalization and CIN.
Noncoding RNA, , Epigenetically Regulates TAL1 Transcriptional Program During Erythropoiesis.
Matur M, Uzun Y, Shi X … +3 more , Hamamoto K, Qiu Y, Huang S
Mol Cell Biol · 2025 · PMID 40211453 · Full text
Hematopoietic transcription is a combinatorial control of transcription factors, chromatin modifiers, and non-coding RNAs. TAL1 is a critical regulator of normal and malignant hematopoiesis. However, mechanism underlying...
Hematopoietic transcription is a combinatorial control of transcription factors, chromatin modifiers, and non-coding RNAs. TAL1 is a critical regulator of normal and malignant hematopoiesis. However, mechanism underlying regulation of TAL1 activity during erythropoiesis versus leukemogenesis remains elusive. Here, we showed that an enhancer RNA, transcribed from Kb-enhancer, is positively correlated with locus chromatin accessibility and transcription, and required for activation during EPO-induced erythropoiesis. Loss of in CD34 hematopoietic stem and progenitor cells leads to reduction of transcription, followed by impaired terminal erythroid differentiation. The effect of loss on erythroid differentiation is partially rescued by overexpression of cDNA, suggesting an important role of /TAL1 regulatory axis in erythropoiesis. Mechanistically, regulates long-range chromatin interactions between Kb erythroid-specific enhancer, promoter and other regulatory elements in the locus to maintain the erythroid interaction hub. By facilitating the binding and recruitment of p300/BRG1 to the locus, promotes chromatin accessibility in the locus and activates transcription program, including subsequent epigenetic and transcriptional activation of erythroid-specific TAL1 target genes. Our study reveals a novel role for in TAL1 dependent erythropoiesis and establishes a new mode of action in transcriptional activation.
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