Advances in biological regulation最新文献

{"title":"Expanding functions of the phosphatidylinositol/phosphatidate lipid transporter, PITPNC1 in physiology and in pathology","authors":"Shamshad Cockcroft","doi":"10.1016/j.jbior.2024.101056","DOIUrl":"10.1016/j.jbior.2024.101056","url":null,"abstract":"<div><div>PITPNC1 was the last of the PITPs to be identified and has been characterized as a binding protein for phosphatidylinositol and phosphatidate. In mammals, PITPNC1 is expressed as two splice variants whilst in zebrafish is expressed from two separate genes. The two splice variants have different expression profiles with the long splice variant having a prominent role in the brain. Several physiological functions have been identified including neuronal and metabolic functions. PITPNC1 also plays a significant role in cancer and has been identified as a risk factor in type 2 diabetes. Here, we review our current understanding of PITPNC1 in cell physiology and pathology.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101056"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455613","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Group photo","authors":"","doi":"10.1016/j.jbior.2025.101078","DOIUrl":"10.1016/j.jbior.2025.101078","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101078"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Key to photograph of participants from left to right of the photo","authors":"","doi":"10.1016/j.jbior.2025.101079","DOIUrl":"10.1016/j.jbior.2025.101079","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101079"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways","authors":"Fumio Sakane ,&nbsp;Chiaki Murakami ,&nbsp;Hiromichi Sakai","doi":"10.1016/j.jbior.2024.101054","DOIUrl":"10.1016/j.jbior.2024.101054","url":null,"abstract":"<div><div>Diacylglycerol kinase (DGK) phosphorylates diacylglycerol (DG) to produce phosphatidic acid (PA). Mammalian DGK comprise ten isozymes (α–κ) that regulate a wide variety of physiological and pathological events. Recently, we revealed that DGK isozymes use saturated fatty acid (SFA)/monosaturated fatty acid (MUFA)-containing and docosahexaenoic acid (22:6)-containing DG species, but not phosphatidylinositol (PI) turnover-derived 18:0/20:4-DG. For example, DGKδ, which is involved in the pathogenesis of type 2 diabetes, preferentially uses SFA/MUFA-containing DG species, such as 16:0/16:0- and 16:0/18:1-DG species, in high glucose-stimulated skeletal muscle cells. Moreover, DGKδ, which destabilizes the serotonin transporter (SERT) and regulates the serotonergic system in the brain, primarily generates 18:0/22:6-PA. Furthermore, 16:0/16:0-PA is produced by DGKζ in Neuro-2a cells during neuronal differentiation. We searched for SFA/MUFA-PA- and 18:0/22:6-PA-selective binding proteins (candidate downstream targets of DGKδ) and found that SFA/MUFA-PA binds to and activates the creatine kinase muscle type, an energy-metabolizing enzyme, and that 18:0/22:6-PA interacts with and activates Praja-1, an E3 ubiquitin ligase acting on SERT, and synaptojanin-1, a key player in the synaptic vesicle cycle. Next, we searched for SFA/MUFA-DG-generating enzymes upstream of DGKδ. We found that sphingomyelin synthase (SMS)1, SMS2, and SMS-related protein (SMSr) commonly act as phosphatidylcholine (PC)-phospholipase C (PLC) and phosphatidylethanolamine (PE)-PLC, generating SFA/MUFA-DG species, in addition to SMS and ceramide phosphoethanolamine synthase. Moreover, the orphan phosphatase PHOSPHO1 showed PC- and PE-PLC activities that produced SFA/MUFA-DG. Although PC- and PE-PLC activities were first described 70–35 years ago, their proteins and genes were not identified for a long time. We found that DGKδ interacts with SMSr and PHOSPHO1, and that DGKζ binds to SMS1 and SMSr. Taken together, these results strongly suggest that there are previously unrecognized signal transduction pathways that include DGK isozymes and generate and utilize SFA/MUFA-DG/PA or 18:0/22:6-DG/PA but not PI-turnover-derived 18:0/20:4-DG/PA.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101054"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142378970","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TP53 gene status can promote sensitivity and resistance to chemotherapeutic drugs and small molecule signal transduction inhibitors","authors":"James A. McCubrey ,&nbsp;Matilde Y. Follo ,&nbsp;Stefano Ratti ,&nbsp;Alberto M. Martelli ,&nbsp;Lucia Manzoli ,&nbsp;Giuseppa Augello ,&nbsp;Melchiorre Cervello ,&nbsp;Lucio Cocco","doi":"10.1016/j.jbior.2024.101073","DOIUrl":"10.1016/j.jbior.2024.101073","url":null,"abstract":"<div><div>TP53 is normally a tumor suppressor. However, it is mutated in at least 50% of human cancers. Usually, we assume that mutation of the TP53 is associated with loss of sensitivity to various drugs as in most cases wild type (WT) TP53 activity is lost. This type of mutations is often dominant-negative (DN) mutations as they can interfere with the normal functions of WT-TP53 which acts as a tetramer. These mutations can result in altered gene expression patterns. There are some TP53 mutations which may lack some of the normal functions of TP53 but have additional functions; these types of mutations are called gain of function (GOF) mutations. There is another class of TP53 mutations, they are TP53 null mutations as the cells have deleted the TP53 gene (TP53-null). Although TP53 mutations were initially considered undruggable, other approaches have been developed to increase TP53 activity. One approach was to develop mouse double minute 2 homolog (MDM2) inhibitors as MDM2 suppresses TP53 activity. In addition, there have been mutant TP53 reactivators created, which will at least partially restore some of the critical growth suppressing effects of TP53. Some of these mutant TP53 reactivators have shown promise in clinical trial in certain types of cancer patients, especially myelodysplastic syndrome (MDS). In this review, we summarize the development of novel TP53 reactivators and MDM2 inhibitors. Both approaches are aimed at increasing or restoring TP53 activity. Attempts to increase TP53 activity in various TP53 mutant tumors could increase therapy of multiple deadly diseases.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101073"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142982414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperactivation of NF-κB signaling in splicing factor mutant myelodysplastic syndromes and therapeutic approaches","authors":"Andrea Pellagatti,&nbsp;Jacqueline Boultwood","doi":"10.1016/j.jbior.2024.101055","DOIUrl":"10.1016/j.jbior.2024.101055","url":null,"abstract":"<div><div>The transcription factor NF-κB plays a critical role in the control of innate and adaptive immunity and inflammation. Several recent studies have demonstrated that the mutation of different splicing factor genes, including <em>SF3B1</em>, <em>SRSF2</em> and <em>U2AF1</em>, in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) result in hyperactive NF-κB signaling through the aberrant splicing of different target genes. The presence of <em>U2AF1</em> and <em>SF3B1</em> mutations in the bone marrow cells of MDS and AML patients induces oncogenic isoforms of the target gene <em>IRAK4</em>, leading to hyperactivation of NF-κB signaling and an increase in the fitness of leukemic stem and progenitor cells (LSPCs). The potent IRAK4 inhibitor CA-4948 has shown efficacy in both pre-clinical studies and MDS clinical trials, with splicing factor mutant patients showing the higher response rates. Emerging data has, however, revealed that co-targeting of IRAK4 and its paralog IRAK1 is required to maximally suppress LSPC function <em>in vitro</em> and <em>in vivo</em> by inducing cellular differentiation. These findings provide a link between the presence of the commonly mutated splicing factor genes and activation of innate immune signaling pathways in myeloid malignancies and have important implications for targeted therapy in these disorders.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101055"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142455614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lamins and chromatin join forces","authors":"Baihui Wang,&nbsp;Qiang Luo,&nbsp;Ohad Medalia","doi":"10.1016/j.jbior.2024.101059","DOIUrl":"10.1016/j.jbior.2024.101059","url":null,"abstract":"<div><div>The intricate interplay between lamins and chromatin underpins the structural integrity and functional organization of the eukaryotic nucleus. Lamins, type V intermediate filament proteins, form a robust meshwork beneath the inner nuclear membrane that is crucial for sustaining nuclear architecture through interactions with lamin-associated domains (LADs). LADs are predominantly heterochromatic regions in which compacted chromatin is enriched at the nuclear periphery, interacting with lamins and lamin-associated proteins. Disruptions of these interactions are implicated in a spectrum of diseases, including laminopathies, cancer, and age-related pathologies, highlighting the importance of lamin-LAD interactions. Thus, a detailed understanding of lamin-chromatin interactions may provide new insights into chromatin organization and shed light on the mechanism behind certain disease states. Here, we discuss the current state of knowledge of lamin-chromatin interactions from a biochemical and structural point of view.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101059"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular basis of JAK kinase regulation guiding therapeutic approaches: Evaluating the JAK3 pseudokinase domain as a drug target","authors":"Anniina Virtanen ,&nbsp;Vivian Kettunen ,&nbsp;Kirsikka Musta ,&nbsp;Veera Räkköläinen ,&nbsp;Stefan Knapp ,&nbsp;Teemu Haikarainen ,&nbsp;Olli Silvennoinen","doi":"10.1016/j.jbior.2024.101072","DOIUrl":"10.1016/j.jbior.2024.101072","url":null,"abstract":"<div><div>Janus kinases (JAK1-3, TYK2) are critical mediators of cytokine signaling and their role in hematological and inflammatory and autoimmune diseases has sparked widespread interest in their therapeutic targeting. JAKs have unique tandem kinase structure consisting of an active tyrosine kinase domain adjacent to a pseudokinase domain that is a hotspot for pathogenic mutations. The development of JAK inhibitors has focused on the active kinase domain and the developed drugs have demonstrated good clinical efficacy but due to off-target inhibition cause also side-effects and carry a black box warning limiting their use. Our understanding of the regulatory function of the pseudokinase domain in physiological and pathological signaling has improved substantially. The pseudokinase domain maintains the inactive state of JAKs in the absence of cytokine stimulation but it has also a key role in physiological and mutation-driven activation process. Furthermore, the pseudokinase domain has favourable structural characteristics for selective targeting of cytokine signaling, such as unique mode of ATP-binding, and the first pseudokinase targeting inhibitor for TYK2 has been approved for clinical use. Here we describe the recent functional and structural knowledge of JAK signaling and their therapeutic targeting, and present data evaluating the druggability of the JAK3 pseudokinase domain.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101072"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142926294","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cellular responses to low nutrient conditions via activation of lysophosphatidic acid (LPA) receptor signaling in gastric cancer cells","authors":"Narumi Yashiro,&nbsp;Miwa Takai,&nbsp;Mao Yamamoto,&nbsp;Yuka Kusumoto,&nbsp;Shion Nagano,&nbsp;Anri Taniguchi,&nbsp;Moemi Tamura,&nbsp;Toshifumi Tsujiuchi","doi":"10.1016/j.jbior.2024.101068","DOIUrl":"10.1016/j.jbior.2024.101068","url":null,"abstract":"<div><div>In the center of the solid tumor, abnormal vascular architecture impedes sufficient blood supply, leading to continuous hypoxia and nutrient deprivation for the tumor cells. Lysophosphatidic acid (LPA) receptor signaling is known to drive a range of malignant behaviors in cancer cells. This study aimed to explore the impact of LPA receptors on cellular functions in gastric cancer AGS cells cultured under low nutrient conditions. When AGS cells were cultured in media containing low glucose (2000 mg/L), low glutamine (1 mM), or low amino acids (50 % content), LPA receptor expression levels were significantly altered. The growth activity of AGS cells cultured in low glucose- and low amino acid-containing media was suppressed by LPA. Conversely, LPA increased the growth activity of AGS cells cultured in low glutamine-containing media. AGS cell motility increased under low glucose and low glutamine conditions, while low amino acid conditions decreased cell motility. Additionally, the viability of AGS cells in response to cisplatin (CDDP) was enhanced under low glucose, low glutamine, and low amino acid conditions. The motility and viability of AGS cells in response to CDDP were significantly increased by AM966 (LPA₁ antagonist), GRI-977143 (LPA₂ agonist) and (2S)-OMPT (LPA₃ agonist). These results suggest that LPA receptor signaling is significantly implicated in regulating malignant properties in AGS cells under low nutrient conditions.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"96 ","pages":"Article 101068"},"PeriodicalIF":0.0,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142759699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state","authors":"Saber Gharagozlou ,&nbsp;NicolaA.M. Wright ,&nbsp;Luis Murguia-Favela ,&nbsp;Juliette Eshleman ,&nbsp;Julian Midgley ,&nbsp;Seha Saygili ,&nbsp;Georgie Mathew ,&nbsp;Harry Lesmana ,&nbsp;Nadia Makkoukdji ,&nbsp;Melissa Gans ,&nbsp;Julie D. Saba","doi":"10.1016/j.jbior.2024.101058","DOIUrl":"10.1016/j.jbior.2024.101058","url":null,"abstract":"<div><div>Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in <em>SGPL1</em>, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress. The SPL reaction represents the only exit point of sphingolipid metabolism, and SPL insufficiency causes widespread sphingolipid derangements that could additionally contribute to immunodeficiency. Herein, we review SPLIS, the sphingolipid metabolic pathway, and various roles sphingolipids play in immunity. We then explore SPLIS-related immunodeficiency by analyzing data available in the published literature supplemented by medical record reviews in ten SPLIS children. We found 93% of evaluable SPLIS patients had documented evidence of immunodeficiency. Many of the remainder of cases were unevaluable due to lack of available immunological data. Most commonly, SPLIS patients exhibited lymphopenia and T cell-specific lymphopenia, consistent with the established role of the S1P/S1P1/SPL axis in lymphocyte egress. However, low B and NK cell counts, hypogammaglobulinemia, and opportunistic infections with bacterial, viral and fungal pathogens were observed. Diminished responses to childhood vaccinations were less frequently observed. Screening blood tests quantifying recent thymic emigrants identified some lymphopenic SPLIS patients in the newborn period. Lymphopenia has been reported to improve after cofactor supplementation in some SPLIS patients, indicating upregulation of SPL activity. A variety of treatments including immunoglobulin replacement, prophylactic antimicrobials and special preparation of blood products prior to transfusion have been employed in SPLIS. The diverse immune consequences in SPLIS patients suggest that aberrant S1P signaling may not fully explain the extent of immunodeficiency. Further study will be required to fully elucidate the complex mechanisms underlying SPLIS immunodeficiency and determine the most effective prophylaxis against infection.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"94 ","pages":"Article 101058"},"PeriodicalIF":0.0,"publicationDate":"2024-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142492793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}