Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101071
Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo
Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.
{"title":"Signaling pathways and bone marrow microenvironment in myelodysplastic neoplasms","authors":"Eleonora Ceneri , Alessia De Stefano , Irene Casalin , Carlo Finelli , Antonio Curti , Stefania Paolini , Sarah Parisi , Federica Ardizzoia , Gianluca Cristiano , Jaqueline Boultwood , James A. McCubrey , Pann-Ghill Suh , Giulia Ramazzotti , Roberta Fiume , Stefano Ratti , Lucia Manzoli , Lucio Cocco , Matilde Y. Follo","doi":"10.1016/j.jbior.2024.101071","DOIUrl":"10.1016/j.jbior.2024.101071","url":null,"abstract":"<div><div>Key signaling pathways within the Bone Marrow Microenvironment (BMM), such as Notch, Phosphoinositide-Specific Phospholipase C (PI-PLCs), Transforming Growth Factor β (TGF-β), and Nuclear Factor Kappa B (NF-κB), play a vital role in the progression of Myelodysplastic Neoplasms (MDS). Among the various BMM cell types, Mesenchymal Stromal Cells (MSCs) are particularly central to these pathways. While these signaling routes can independently affect both MSCs and Hematopoietic Stem Cells (HSCs), they most importantly alter the dynamics of their interactions, leading to abnormal changes in survival, differentiation, and quiescence. Notch and PI-PLC signaling facilitate intercellular communication, TGF-β promotes quiescence and suppresses hematopoiesis, and NF-κB-driven inflammatory responses foster an environment detrimental to normal hematopoiesis. This review highlights the role of these pathways within the MDS microenvironment, driving the development and progression of the disease and paving the way for new possible therapeutic strategies.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101071"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794342","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101060
Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams
The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.
磷酸肌酸 3-激酶（PI3K）超家族包括脂质激酶（PI3Ks 和 III 型 PI4Ks）和一组类似 PI3K 的 Ser/Thr 蛋白激酶（PIKKs：mTOR、ATM、ATR、DNA-PKcs、SMG1 和 TRRAP），它们都有一个保守的 C 端激酶结构域。该超家族的一个共同特点是，它们的基础活性很低，但可以通过一系列调节因子大大提高。激活因子会重新配置活性位点，使激酶结构域的 N-叶相对于 C-叶发生微妙的重新排列。这种重新排列使 N 环的 ATP 结合环更接近 C 环的催化残基。此外，被称为 PIKK 调节结构域（PRD）的保守的 C-lobe 特征也会改变构象，PI3K 激活剂也会改变类似的 PRD 区域。最近的结构显示，各种激活影响因素都能引发这些构象变化，而夹在激酶结构域上的螺旋区域则能传递调控相互作用，使活性位点重新排列，从而提高催化效率。最近一份关于应用于神经再生的 PI3Kα 小分子激活剂的报告表明，可以利用这些调节元件的灵活性来开发所有 PI3K 超家族成员的特异性激活剂。这些激活剂可在伤口愈合、抗中风治疗和治疗神经变性方面发挥作用。我们回顾了 PI3K 超家族的共同结构特征，这些特征可能使它们适于激活。
{"title":"Making PI3K superfamily enzymes run faster","authors":"Grace Q. Gong , Madhangopal Anandapadamanaban , Md Saiful Islam , Iain M. Hay , Maxime Bourguet , Saulė Špokaitė , Antoine N. Dessus , Yohei Ohashi , Olga Perisic , Roger L. Williams","doi":"10.1016/j.jbior.2024.101060","DOIUrl":"10.1016/j.jbior.2024.101060","url":null,"abstract":"<div><div>The phosphoinositide 3-kinase (PI3K) superfamily includes lipid kinases (PI3Ks and type III PI4Ks) and a group of PI3K-like Ser/Thr protein kinases (PIKKs: mTOR, ATM, ATR, DNA-PKcs, SMG1 and TRRAP) that have a conserved C-terminal kinase domain. A common feature of the superfamily is that they have very low basal activity that can be greatly increased by a range of regulatory factors. Activators reconfigure the active site, causing a subtle realignment of the N-lobe of the kinase domain relative to the C-lobe. This realignment brings the ATP-binding loop in the N-lobe closer to the catalytic residues in the C-lobe. In addition, a conserved C-lobe feature known as the PIKK regulatory domain (PRD) also can change conformation, and PI3K activators can alter an analogous PRD-like region. Recent structures have shown that diverse activating influences can trigger these conformational changes, and a helical region clamping onto the kinase domain transmits regulatory interactions to bring about the active site realignment for more efficient catalysis. A recent report of a small-molecule activator of PI3Kα for application in nerve regeneration suggests that flexibility of these regulatory elements might be exploited to develop specific activators of all PI3K superfamily members. These activators could have roles in wound healing, anti-stroke therapy and treating neurodegeneration. We review common structural features of the PI3K superfamily that may make them amenable to activation.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101060"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724465","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101070
Danielle M. Smith , Joseph Choi , Michael J. Wolfgang
Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.
{"title":"Tissue specific roles of fatty acid oxidation","authors":"Danielle M. Smith , Joseph Choi , Michael J. Wolfgang","doi":"10.1016/j.jbior.2024.101070","DOIUrl":"10.1016/j.jbior.2024.101070","url":null,"abstract":"<div><div>Mitochondrial long chain fatty acid β-oxidation is a critical central carbon catabolic process. The importance of fatty acid oxidation is made evident by the life-threatening disease associated with diverse inborn errors in the pathway. While inborn errors show multisystemic requirements for fatty acid oxidation, it is not clear from the clinical presentation of these enzyme deficiencies what the tissue specific roles of the pathway are compared to secondary systemic effects. To understand the cell or tissue specific contributions of fatty acid oxidation to systemic physiology, conditional knockouts in mice have been employed to determine the requirements of fatty acid oxidation in disparate cell types. This has produced a host of surprising results that sometimes run counter to the canonical view of this metabolic pathway. The rigor of conditional knockouts has also provided clarity over previous research utilizing cell lines in vitro or small molecule inhibitors with dubious specificity. Here we will summarize current research using mouse models of Carnitine Palmitoyltransferases to determine the tissue specific roles and requirements of long chain mitochondrial fatty acid β-oxidation.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101070"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821765","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2025.101074
George M. Carman, Geordan J. Stukey, Ruta Jog, Gil-Soo Han
Phosphatidic acid phosphatase, a conserved eukaryotic enzyme that catalyzes the Mg2+-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol, has emerged as a vital regulator of lipid homeostasis. By controlling the balance of phosphatidic acid and diacylglycerol, the enzyme governs the use of the lipids for synthesis of the storage lipid triacylglycerol and the membrane phospholipids needed for cell growth. The mutational, biochemical, and cellular analyses of yeast phosphatidic acid phosphatase have provided insights into the structural determinants of enzyme function with the understanding of its regulation by phosphorylation and dephosphorylation. The key role that the enzyme plays in triacylglycerol synthesis indicates it may be a potential drug target to ameliorate obesity in humans. The enzyme activity, which is critical to the growth and virulence of pathogenic fungi, is a proposed target for therapeutic development to ameliorate fungal infections.
{"title":"Insights into phosphatidic acid phosphatase and its potential role as a therapeutic target","authors":"George M. Carman, Geordan J. Stukey, Ruta Jog, Gil-Soo Han","doi":"10.1016/j.jbior.2025.101074","DOIUrl":"10.1016/j.jbior.2025.101074","url":null,"abstract":"<div><div>Phosphatidic acid phosphatase, a conserved eukaryotic enzyme that catalyzes the Mg<sup>2+</sup>-dependent dephosphorylation of phosphatidic acid to produce diacylglycerol, has emerged as a vital regulator of lipid homeostasis. By controlling the balance of phosphatidic acid and diacylglycerol, the enzyme governs the use of the lipids for synthesis of the storage lipid triacylglycerol and the membrane phospholipids needed for cell growth. The mutational, biochemical, and cellular analyses of yeast phosphatidic acid phosphatase have provided insights into the structural determinants of enzyme function with the understanding of its regulation by phosphorylation and dephosphorylation. The key role that the enzyme plays in triacylglycerol synthesis indicates it may be a potential drug target to ameliorate obesity in humans. The enzyme activity, which is critical to the growth and virulence of pathogenic fungi, is a proposed target for therapeutic development to ameliorate fungal infections.</div></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101074"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142942577","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2025.101080
{"title":"Photo of special symposium lecturer - Vytas Bankaitis","authors":"","doi":"10.1016/j.jbior.2025.101080","DOIUrl":"10.1016/j.jbior.2025.101080","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"95 ","pages":"Article 101080"},"PeriodicalIF":0.0,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143421467","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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101056
Shamshad Cockcroft
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.
{"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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2025.101079
{"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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101054
Fumio Sakane , Chiaki Murakami , Hiromichi Sakai
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.
{"title":"Upstream and downstream pathways of diacylglycerol kinase : Novel phosphatidylinositol turnover-independent signal transduction pathways","authors":"Fumio Sakane , Chiaki Murakami , 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}
Pub Date : 2025-01-01DOI: 10.1016/j.jbior.2024.101073
James A. McCubrey , Matilde Y. Follo , Stefano Ratti , Alberto M. Martelli , Lucia Manzoli , Giuseppa Augello , Melchiorre Cervello , Lucio Cocco
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.
{"title":"TP53 gene status can promote sensitivity and resistance to chemotherapeutic drugs and small molecule signal transduction inhibitors","authors":"James A. McCubrey , Matilde Y. Follo , Stefano Ratti , Alberto M. Martelli , Lucia Manzoli , Giuseppa Augello , Melchiorre Cervello , 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}
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