Advances in biological regulation最新文献

{"title":"Targeted pharmacologic inhibition of S-phase kinase-associated protein 2 (SKP2) mediated cell cycle regulation in lung and other RB-Related cancers: A brief review of current status and future prospects","authors":"Abul H. Elahi ,&nbsp;Cordelia S. Morales ,&nbsp;Xiaoliang L. Xu ,&nbsp;Alexia Eliades ,&nbsp;Philippos C. Patsalis ,&nbsp;David H. Abramson ,&nbsp;Suresh C. Jhanwar","doi":"10.1016/j.jbior.2023.100964","DOIUrl":"10.1016/j.jbior.2023.100964","url":null,"abstract":"<div><p>Small cell lung cancer (SCLC) often exhibits Rb deficiency, TRβ and p130 deletion, and SKP2 amplification, suggesting TRβ inactivation and SKP2 activation. It is reported that SKP2 targeted therapy is effective in some cancers in vitro and in vivo, but it is not reported for the treatment of SCLC and retinoblastoma. SKP2 is the synthetic lethal gene in SCLC and retinoblastoma, so SKP2 can be used for targeted therapy in SCLC and retinoblastoma. RB1 knockout mice develop several kinds of tumors, but Rb1 and SKP2 double knockout mice are healthy, suggesting that SKP2 targeted therapy may have significant effects on Rb deficient cancers with less side effects, and if successful in SCLC and retinoblastoma in vitro and in animal model, such compounds may be promising for the clinical treatment of SCLC, retinoblastoma, and variety of Rb deficient cancers.</p><p>Previously our studies showed that retinoblastomas exhibit retinal cone precursor properties and depend on cone-specific thyroid hormone receptor β2 (TRβ2) and SKP2 signaling. In this study, we sought to suppress SCLC and retinoblastoma cell growth by SKP2 inhibitors as a prelude to targeted therapy in vitro and in vivo.</p><p>We knocked down TRβ2 and SKP2 or over-expressed p27 in SCLC and retinoblastoma cell lines to investigate SKP2 and p27 signaling alterations. The SCLC cell lines H209 as well as retinoblastoma cell lines Y79, WERI, and RB177 were treated with SKP2 inhibitor C1 at different concentrations, following which Western blotting, Immunostaining, and cell cycle kinetics studies were performed to study SKP2 and p27 expression ubiquitination, to determine impact on cell cycle regulation and growth inhibition.</p><p>TRβ2 knockdown in Y79, RB177 and H209 caused SKP2 downregulation and degradation, p27 up-regulation, and S phase arrest, whereas, SKP2 knockdown or p27 over-expression caused p27 accumulation and G1-S phase arrest. In the cell lines Y79, WERI, RB177, and H209 treatment with C1 caused SKP2 ubiquitination and degradation, p27 de-ubiquitination and accumulation, and cell growth arrest. SKP2 inhibitor C1 significantly suppressed retinoblastoma as well as SCLC cell growth by SKP2 degradation and p27 accumulation. In vivo study also showed inhibition of tumor growth with C1 treatment. Potential limitations of the success of such a therapeutic approach and its translational application in human primary tumors, and alternative approaches to overcome such limitations are briefly discussed for the treatment of retinoblastoma, SCLC and other RB-related cancers.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"88 ","pages":"Article 100964"},"PeriodicalIF":0.0,"publicationDate":"2023-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9646173","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":"Preclinical models of non-alcoholic steatohepatitis leading to hepatocellular carcinoma","authors":"Christopher D. Green,&nbsp;Sarah Spiegel","doi":"10.1016/j.jbior.2022.100925","DOIUrl":"10.1016/j.jbior.2022.100925","url":null,"abstract":"<div><p>Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide and its incidence is increasing due to endemic obesity and the growing burden of non-alcoholic steatohepatitis (NASH) associated liver cancer. Although much is known about the clinical and histological pathology of NASH-driven HCC in humans, its etiology remains unclear and there is a lack of reliable biomarkers and limited effective therapies. Progress has been hampered by the scarcity of standardized animal models that recapitulate the gradual progression of NASH towards HCC observed in humans. Here we review existing mouse models and their suitability for studying NASH-driven HCC with special emphasis on a preclinical model that we recently developed that faithfully mimics all the clinical endpoints of progression of the human disease. Moreover, it is highly translatable, allows the use of gene-targeted mice, and is suitable for gaining knowledge of how NASH progresses to HCC and development of new targets for treatment.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100925"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10337648/pdf/nihms-1915287.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9771822","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.2022.100950","DOIUrl":"10.1016/j.jbior.2022.100950","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100950"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10461013","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":"Structural investigation of eukaryotic cells: From the periphery to the interior by cryo-electron tomography","authors":"Chunyang Wang,&nbsp;Matthias Wojtynek,&nbsp;Ohad Medalia","doi":"10.1016/j.jbior.2022.100923","DOIUrl":"10.1016/j.jbior.2022.100923","url":null,"abstract":"<div><p>Cryo-electron tomography (cryo-ET) combines a close-to-life preservation of the cell with high-resolution three-dimensional (3D) imaging. This allows to study the molecular architecture of the cellular landscape and provides unprecedented views on biological processes and structures. In this review we mainly focus on the application of cryo-ET to visualize and structurally characterize eukaryotic cells – from the periphery to the cellular interior. We discuss strategies that can be employed to investigate the structure of challenging targets in their cellular environment as well as the application of complimentary approaches in conjunction with cryo-ET.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100923"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9166477","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":"Effects of chloroquine and hydroxychloroquine on the sensitivity of pancreatic cancer cells to targeted therapies","authors":"James A. McCubrey ,&nbsp;Stephen L. Abrams ,&nbsp;Matilde Y. Follo ,&nbsp;Lucia Manzoli ,&nbsp;Stefano Ratti ,&nbsp;Alberto M. Martelli ,&nbsp;Melchiorre Cervello","doi":"10.1016/j.jbior.2022.100917","DOIUrl":"10.1016/j.jbior.2022.100917","url":null,"abstract":"<div><p>Approaches to improve pancreatic cancer therapy are essential as this disease has a very bleak outcome. Approximately 80% of pancreatic cancers are pancreatic ductal adenocarcinomas (PDAC). PDAC is a cancer which is difficult to effectively treat as it is often detected late in the disease process. Almost all PDACs (over 90%) have activating mutations in the GTPase gene <em>KRAS</em>. These mutations result in constitutive KRas activation and the mobilization of downstream pathways such as the Raf/MEK/ERK pathway. Small molecule inhibitors of key components of the KRas/Raf/MEK/ERK pathways as well as monoclonal antibodies (MoAbs) specific for upstream growth factor receptors such insulin like growth factor-1 receptor (IGF1-R) and epidermal growth factor receptors (EGFRs) have been developed and have been evaluated in clinical trials. An additional key regulatory gene frequently mutated (∼75%) in PDAC is the <em>TP53</em> tumor suppressor gene which controls the transcription of multiple genes involved in cell cycle progression, apoptosis, metabolism, cancer progression and other growth regulatory processes. Small molecule mutant TP53 reactivators have been developed which alter the structure of mutant TP53 protein and restore some of its antiproliferative activities. Some mutant TP53 reactivators have been examined in clinical trials with patients with mutant TP53 genes. Inhibitors to the TP53 negative regulator Mouse Double Minute 2 (MDM2) have been developed and analyzed in clinical trials. Chloroquine and hydroxychloroquine are established anti-malarial and anti-inflammatory drugs that also prevent the induction of autophagy which can have effects on cancer survival. Chloroquine and hydroxychloroquine have also been examined in various clinical trials. Recent studies are suggesting effective treatment of PDAC patients may require chemotherapy as well as targeting multiple pathways and biochemical processes.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100917"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9226110","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":"Regulations of myo-inositol homeostasis: Mechanisms, implications, and perspectives","authors":"Xue Bessie Su,&nbsp;An-Li Andrea Ko,&nbsp;Adolfo Saiardi","doi":"10.1016/j.jbior.2022.100921","DOIUrl":"10.1016/j.jbior.2022.100921","url":null,"abstract":"<div><p>Phosphorylation is the most common module of cellular signalling pathways. The dynamic nature of phosphorylation, which is conferred by the balancing acts of kinases and phosphatases, allows this modification to finely control crucial cellular events such as growth, differentiation, and cell cycle progression. Although most research to date has focussed on protein phosphorylation, non-protein phosphorylation substrates also play vital roles in signal transduction. The most well-established substrate of non-protein phosphorylation is inositol, whose phosphorylation generates many important signalling molecules such as the second messenger IP₃, a key factor in calcium signalling.</p><p>A fundamental question to our understanding of inositol phosphorylation is how the levels of cellular inositol are controlled. While the availability of protein phosphorylation substrates is known to be readily controlled at the levels of transcription, translation, and/or protein degradation, the regulatory mechanisms that control the uptake, synthesis, and removal of inositol are underexplored. Potentially, such mechanisms serve as an important layer of regulation of cellular signal transduction pathways.</p><p>There are two ways in which mammalian cells acquire inositol. The historic use of radioactive ³H-<em>myo</em>-inositol revealed that inositol is promptly imported from the extracellular environment by three specific symporters SMIT1/2, and HMIT, coupling sodium or proton entry, respectively. Inositol can also be synthesized <em>de novo</em> from glucose-6P, thanks to the enzymatic activity of ISYNA1. Intriguingly, emerging evidence suggests that in mammalian cells, <em>de novo myo</em>-inositol synthesis occurs irrespective of inositol availability in the environment, prompting the question of whether the two sources of inositol go through independent metabolic pathways, thus serving distinct functions. Furthermore, the metabolic stability of <em>myo</em>-inositol, coupled with the uptake and endogenous synthesis, determines that there must be exit pathways to remove this extraordinary sugar from the cells to maintain its homeostasis. This essay aims to review our current knowledge of <em>myo</em>-inositol homeostatic metabolism, since they are critical to the signalling events played by its phosphorylated forms.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100921"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9173478","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":"Spiegel photo","authors":"","doi":"10.1016/j.jbior.2022.100953","DOIUrl":"10.1016/j.jbior.2022.100953","url":null,"abstract":"","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100953"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10461015","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":"Splicing factor mutations in the myelodysplastic syndromes: Role of key aberrantly spliced genes in disease pathophysiology and treatment","authors":"Andrea Pellagatti,&nbsp;Jacqueline Boultwood","doi":"10.1016/j.jbior.2022.100920","DOIUrl":"10.1016/j.jbior.2022.100920","url":null,"abstract":"<div><p>Mutations of splicing factor genes (including <em>SF3B1</em>, <em>SRSF2</em>, <em>U2AF1</em> and <em>ZRSR2</em>) occur in more than half of all patients with myelodysplastic syndromes (MDS), a heterogeneous group of myeloid neoplasms. Splicing factor mutations lead to aberrant pre-mRNA splicing of many genes, some of which have been shown in functional studies to impact on hematopoiesis and to contribute to the MDS phenotype. This clearly demonstrates that impaired spliceosome function plays an important role in MDS pathophysiology. Recent studies that harnessed the power of induced pluripotent stem cell (iPSC) and CRISPR/Cas9 gene editing technologies to generate new iPSC-based models of splicing factor mutant MDS, have further illuminated the role of key downstream target genes. The aberrantly spliced genes and the dysregulated pathways associated with splicing factor mutations in MDS represent potential new therapeutic targets. Emerging data has shown that <em>IRAK4</em> is aberrantly spliced in <em>SF3B1</em> and <em>U2AF1</em> mutant MDS, leading to hyperactivation of NF-κB signaling. Pharmacological inhibition of IRAK4 has shown efficacy in pre-clinical studies and in MDS clinical trials, with higher response rates in patients with splicing factor mutations. Our increasing knowledge of the effects of splicing factor mutations in MDS is leading to the development of new treatments that may benefit patients harboring these mutations.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100920"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10583466","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":"Regulation of eukaryotic protein kinases by Pin1, a peptidyl-prolyl isomerase","authors":"Xiao-Ru Chen,&nbsp;Tatyana I. Igumenova","doi":"10.1016/j.jbior.2022.100938","DOIUrl":"10.1016/j.jbior.2022.100938","url":null,"abstract":"<div><p>The peptidyl-prolyl isomerase Pin1 cooperates with proline-directed kinases and phosphatases to regulate multiple oncogenic pathways. Pin1 specifically recognizes phosphorylated Ser/Thr-Pro motifs in proteins and catalyzes their <em>cis</em>-<em>trans</em> isomerization. The Pin1-catalyzed conformational changes determine the stability, activity, and subcellular localization of numerous protein substrates. We conducted a survey of eukaryotic protein kinases that are regulated by Pin1 and whose Pin1 binding sites have been identified. Our analyses reveal that Pin1 target sites in kinases do not fall exclusively within the intrinsically disordered regions of these enzymes. Rather, they fall into three groups based on their location: (i) within the catalytic kinase domain, (ii) in the C-terminal kinase region, and (iii) in regulatory domains. Some of the kinases downregulated by Pin1 activity are tumor-suppressing, and all kinases upregulated by Pin1 activity are functionally pro-oncogenic. These findings further reinforce the rationale for developing Pin1-specific inhibitors as attractive pharmaceuticals for cancer therapy.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100938"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9992314/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9174115","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":"IL-7 and IL-7R in health and disease: An update through COVID times","authors":"Marta B. Fernandes,&nbsp;João T. Barata","doi":"10.1016/j.jbior.2022.100940","DOIUrl":"10.1016/j.jbior.2022.100940","url":null,"abstract":"<div><p>The role of IL-7 and IL-7R for normal lymphoid development and an adequately functioning immune system has been recognized for long, with severe immune deficiency and lymphoid leukemia as extreme examples of the consequences of deregulation of the IL-7-IL-7R axis. In this review, we provide an update (focusing on the past couple of years) on IL-7 and IL-7R in health and disease. We highlight the findings on IL-7/IL-7R signaling mechanisms and the, sometimes controversial, impact of IL-7 and its receptor on leukocyte biology, COVID-19, acute lymphoblastic leukemia, and different solid tumors, as well as their relevance as therapeutic tools or targets.</p></div>","PeriodicalId":7214,"journal":{"name":"Advances in biological regulation","volume":"87 ","pages":"Article 100940"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9174117","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}