scholarly journals Therapeutic Approaches Targeting Nucleolus in Cancer

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1090 ◽  
Author(s):  
Pietro Carotenuto ◽  
Annalisa Pecoraro ◽  
Gaetano Palma ◽  
Giulia Russo ◽  
Annapina Russo
Keyword(s):  
Stress Responses ◽  
Ribosome Biogenesis ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Therapeutic Interventions ◽  
Main Function ◽  
Therapeutic Approaches ◽  
Functional Studies ◽  
Cellular Processes ◽  
Histopathological Studies

The nucleolus is a distinct sub-cellular compartment structure in the nucleus. First observed more than 200 years ago, the nucleolus is detectable by microscopy in eukaryotic cells and visible during the interphase as a sub-nuclear structure immersed in the nucleoplasm, from which it is not separated from any membrane. A huge number of studies, spanning over a century, have identified ribosome biogenesis as the main function of the nucleolus. Recently, novel functions, independent from ribosome biogenesis, have been proposed by several proteomic, genomic, and functional studies. Several works have confirmed the non-canonical role for nucleoli in regulating important cellular processes including genome stability, cell-cycle control, the cellular senescence, stress responses, and biogenesis of ribonucleoprotein particles (RNPs). Many authors have shown that both canonical and non-canonical functions of the nucleolus are associated with several cancer-related processes. The association between the nucleolus and cancer, first proposed by cytological and histopathological studies showing that the number and shape of nucleoli are commonly altered in almost any type of cancer, has been confirmed at the molecular level by several authors who demonstrated that numerous mechanisms occurring in the nucleolus are altered in tumors. Recently, therapeutic approaches targeting the nucleolus in cancer have started to be considered as an emerging “hallmark” of cancer and several therapeutic interventions have been developed. This review proposes an up-to-date overview of available strategies targeting the nucleolus, focusing on novel targeted therapeutic approaches. Finally, a target-based classification of currently available treatment will be proposed.

scholarly journals Ubiquitin proteomics reveals critical targets of the Nse1 RING domain in rDNA and genome stability

2021 ◽  
Author(s):  
Eva Ibars ◽  
Gemma Belli ◽  
Celia Casas ◽  
Joan Codina-Fabra ◽  
Marc Tarres ◽  
...  
Keyword(s):  
Ribosome Biogenesis ◽  
Genome Stability ◽  
Ring Domain ◽  
Transcriptional Elongation ◽  
Label Free ◽  
Dna Damage Tolerance ◽  
Cellular Processes ◽  
Ubiquitin E3 Ligase ◽  
Polymerase I ◽  
Mutant Cells

Ubiquitination controls numerous cellular processes, and its deregulation is associated to many pathologies. The Nse1 subunit in the Smc5/6 complex contains a RING domain with ubiquitin E3 ligase activity and important functions in genome integrity. However, Nse1-dependent ubiquitin targets remain largely unknown. Here, we use label-free quantitative proteomics to analyse the nuclear ubiquitinome of nse1-C274A RING mutant cells. Our results show that Nse1 impacts on the ubiquitination of several proteins involved in DNA damage tolerance, ribosome biogenesis and metabolism that, importantly, extend beyond canonical functions of the Smc5/6 complex in chromosome segregation. In addition, our analysis uncovers an unexpected connection between Nse1 and RNA polymerase I (RNAP I) ubiquitination. Specifically, Nse1 promotes the ubiquitination of K408 and K410 in A190, the largest subunit of RNAP I, to induce its degradation. We propose that this mechanism contributes to Smc5/6-dependent rDNA disjunction in response to transcriptional elongation defects.

scholarly journals Emerging concepts of nucleolar assembly

2002 ◽  
Vol 115 (11) ◽  
pp. 2265-2270 ◽  
Author(s):  
Danièle Hernandez-Verdun ◽  
Pascal Roussel ◽  
Jeannine Gébrane-Younès
Keyword(s):  
Cell Cycle ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Cycle Progression ◽  
Cooperative Interactions ◽  
Cellular Processes ◽  
Nuclear Domain ◽  
New Ideas

The nucleolus is a large nuclear domain and the site of ribosome biogenesis. It is also at the parting of the ways of several cellular processes, including cell cycle progression, gene silencing, and ribonucleoprotein complex formation. Consequently, a functional nucleolus is crucial for cell survival. Recent investigations of nucleolar assembly during the cell cycle and during embryogenesis have provided an integrated view of the dynamics of this process. Moreover, they have generated new ideas about cell cycle control of nucleolar assembly, the dynamics of the delivery of the RNA processing machinery, the formation of prenucleolar bodies, the role of precursor ribosomal RNAs in stabilizing the nucleolar machinery and the fact that nucleolar assembly is completed by cooperative interactions between chromosome territories. This has opened a new area of research into the dynamics of nuclear organization and the integration of nuclear functions.

scholarly journals The ATR-WEE1 kinase module inhibits the MAC complex to regulate replication stress response

2021 ◽  
Vol 49 (3) ◽  
pp. 1411-1425 ◽  
Author(s):  
Lili Wang ◽  
Li Zhan ◽  
Yan Zhao ◽  
Yongchi Huang ◽  
Chong Wu ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Stress Responses ◽  
Genome Stability ◽  
Intron Retention ◽  
Cell Cycle Control ◽  
Replication Stress ◽  
Loss Of Function ◽  
Evolutionarily Conserved ◽  
Subsequent Degradation ◽  
Wee1 Kinase

Abstract DNA damage response is a fundamental mechanism to maintain genome stability. The ATR-WEE1 kinase module plays a central role in response to replication stress. Although the ATR-WEE1 pathway has been well studied in yeasts and animals, how ATR-WEE1 functions in plants remains unclear. Through a genetic screen for suppressors of the Arabidopsis atr mutant, we found that loss of function of PRL1, a core subunit of the evolutionarily conserved MAC complex involved in alternative splicing, suppresses the hypersensitivity of atr and wee1 to replication stress. Biochemical studies revealed that WEE1 directly interacts with and phosphorylates PRL1 at Serine 145, which promotes PRL1 ubiquitination and subsequent degradation. In line with the genetic and biochemical data, replication stress induces intron retention of cell cycle genes including CYCD1;1 and CYCD3;1, which is abolished in wee1 but restored in wee1 prl1. Remarkably, co-expressing the coding sequences of CYCD1;1 and CYCD3;1 partially restores the root length and HU response in wee1 prl1. These data suggested that the ATR-WEE1 module inhibits the MAC complex to regulate replication stress responses. Our study discovered PRL1 or the MAC complex as a key downstream regulator of the ATR-WEE1 module and revealed a novel cell cycle control mechanism.

scholarly journals Regulation of Sli15/INCENP, kinetochore, and Cdc14 phosphatase functions by the ribosome biogenesis protein Utp7

2008 ◽  
Vol 182 (6) ◽  
pp. 1099-1111 ◽  
Author(s):  
Miri Jwa ◽  
Jae-hyun Kim ◽  
Clarence S.M. Chan
Keyword(s):  
Chromosome Segregation ◽  
Ribosome Biogenesis ◽  
Cell Cycle Control ◽  
Yeast Saccharomyces Cerevisiae ◽  
Multifunctional Protein ◽  
Cellular Processes ◽  
Microtubule Attachment ◽  
Chromosomal Passenger ◽  
Early Anaphase ◽  
Spindle Stability

The Sli15–Ipl1–Bir1 chromosomal passenger complex is essential for proper kinetochore–microtubule attachment and spindle stability in the budding yeast Saccharomyces cerevisiae. During early anaphase, release of the Cdc14 protein phosphatase from the nucleolus leads to the dephosphorylation of Sli15 and redistribution of this complex from kinetochores to the spindle. We show here that the predominantly nucleolar ribosome biogenesis protein Utp7 is also present at kinetochores and is required for normal organization of kinetochore proteins and proper chromosome segregation. Utp7 associates with and regulates the localization of Sli15 and Cdc14. Before anaphase onset, it prevents the premature nucleolar release of Cdc14 and the premature concentration of Sli15 on the spindle. Furthermore, Utp7 can regulate the localization and phosphorylation status of Sli15 independent of its effect on Cdc14 function. Thus, Utp7 is a multifunctional protein that plays essential roles in the vital cellular processes of ribosome biogenesis, chromosome segregation, and cell cycle control.

scholarly journals Current Implications of microRNAs in Genome Stability and Stress Responses of Ovarian Cancer

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2690
Author(s):  
Arkadiusz Gajek ◽  
Patrycja Gralewska ◽  
Agnieszka Marczak ◽  
Aneta Rogalska
Keyword(s):  
Ovarian Cancer ◽  
Dna Damage ◽  
Stress Response ◽  
Stress Responses ◽  
Genome Stability ◽  
Replication Stress ◽  
Parp Inhibitors ◽  
Multiple Cancer ◽  
Cellular Processes ◽  
Effective Combination

Genomic alterations and aberrant DNA damage signaling are hallmarks of ovarian cancer (OC), the leading cause of mortality among gynecological cancers worldwide. Owing to the lack of specific symptoms and late-stage diagnosis, survival chances of patients are significantly reduced. Poly (ADP-ribose) polymerase (PARP) inhibitors and replication stress response inhibitors present attractive therapeutic strategies for OC. Recent research has focused on ovarian cancer-associated microRNAs (miRNAs) that play significant regulatory roles in various cellular processes. While miRNAs have been shown to participate in regulation of tumorigenesis and drug responses through modulating the DNA damage response (DDR), little is known about their potential influence on sensitivity to chemotherapy. The main objective of this review is to summarize recent findings on the utility of miRNAs as cancer biomarkers, in particular, ovarian cancer, and their regulation of DDR or modified replication stress response proteins. We further discuss the suppressive and promotional effects of various miRNAs on ovarian cancer and their participation in cell cycle disturbance, response to DNA damage, and therapeutic functions in multiple cancer types, with particular focus on ovarian cancer. Improved understanding of the mechanisms by which miRNAs regulate drug resistance should facilitate the development of effective combination therapies for ovarian cancer.

Coronary Artery Disease and Endothelial Dysfunction: Novel Diagnostic and Therapeutic Approaches

2020 ◽  
Vol 27 (7) ◽  
pp. 1052-1080 ◽  
Author(s):  
Evangelos Oikonomou ◽  
Gerasimos Siasos ◽  
Vasiliki Tsigkou ◽  
Evanthia Bletsa ◽  
Maria-Evi Panoilia ◽  
...  
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Stable Coronary Artery Disease ◽  
Therapeutic Interventions ◽  
Therapeutic Approaches ◽  
Cardiovascular Prognosis ◽  
Ultrasound Evaluation ◽  
Artery Disease

Coronary artery disease is the leading cause of morbidity and mortality worldwide. The most common pathophysiologic substrate is atherosclerosis which is an inflammatory procedure that starts at childhood and develops throughout life. Endothelial dysfunction is associated with the initiation and progression of atherosclerosis and is characterized by the impaired production of nitric oxide. In general, endothelial dysfunction is linked to poor cardiovascular prognosis and different methods, both invasive and non-invasive, have been developed for its evaluation. Ultrasound evaluation of flow mediated dilatation of the branchial artery is the most commonly used method to assessed endothelial function while intracoronary administration of vasoactive agents may be also be used to test directly endothelial properties of the coronary vasculature. Endothelial dysfunction has also been the subject of therapeutic interventions. This review article summarizes the knowledge about evaluation of endothelial function in acute coronary syndromes and stable coronary artery disease and demonstrates the current therapeutic approaches against endothelial dysfunction.

The Epitome of Novel Techniques and Targeting Approaches in Drug Delivery for Treating Lymphatic Filariasis

2020 ◽  
Vol 21 (12) ◽  
pp. 1250-1263
Author(s):  
Saurabh Shrivastava ◽  
Anshita Gupta ◽  
Chanchal Deep Kaur
Keyword(s):  
Lymphatic Filariasis ◽  
Neglected Tropical Diseases ◽  
Therapeutic Interventions ◽  
Tropical Diseases ◽  
Human Beings ◽  
Therapeutic Approaches ◽  
Preventive Chemotherapy ◽  
Bioactive Substances ◽  
Lymphatic Diseases ◽  
Life Threatening

Background: Lymphatic filariasis is a pervasive and life-threatening disease for human beings. Currently, 893 million people in 49 countries worldwide affected by lymphatic filariasis as per WHO statistics. The concealed aspects of lymphatic diseases such as delayed disease detection, inappropriate disease imaging, the geographical outbreak of infection, and lack of preventive chemotherapy have brought this epidemic to the edge of Neglected Tropical Diseases. Many medications and natural bioactive substances have seen to promote filaricidal activity against the target parasitic species. However, the majority of failures have occurred in pharmaceutical and pharmacokinetic issues. Objective: The purpose of the study is to focus on the challenges and therapeutic issues in the treatment of filariasis. The review brings novel techniques and therapeutic approaches for combating lymphatic filariasis. It also offers significant developments and opportunities for such therapeutic interventions. Conclusion: Through this review, an attempt has made to critically evaluate the avenues of innovative pharmaceuticals and molecular targeting approaches to bring an integrated solution to combat lymphatic filariasis.

scholarly journals Pediatric leukemia susceptibility disorders: manifestations and management

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 242-250 ◽  
Author(s):  
Lisa J. McReynolds ◽  
Sharon A. Savage
Keyword(s):  
Early Onset ◽  
Ribosome Biogenesis ◽  
De Novo ◽  
Disease Risk ◽  
Bone Marrow Failure ◽  
Clinical Manifestations ◽  
Cancer Surveillance ◽  
Therapeutic Interventions ◽  
Pediatric Leukemia ◽  
Inherited Susceptibility

Abstract The clinical manifestations of inherited susceptibility to leukemia encompass a wide phenotypic range, including patients with certain congenital anomalies or early-onset myelodysplastic syndrome (MDS) and some with no obvious medical problems until they develop leukemia. Leukemia susceptibility syndromes occur as a result of autosomal dominant, autosomal recessive, or X-linked recessive inheritance, or de novo occurrence, of germline pathogenic variants in DNA repair, ribosome biogenesis, telomere biology, hematopoietic transcription factors, tumor suppressors, and other critical cellular processes. Children and adults with cytopenias, MDS, dysmorphic features, notable infectious histories, immunodeficiency, certain dermatologic findings, lymphedema, unusual sensitivity to radiation or chemotherapy, or acute leukemia with a family history of early-onset cancer, pulmonary fibrosis, or alveolar proteinosis should be thoroughly evaluated for a leukemia susceptibility syndrome. Genetic testing and other diagnostic modalities have improved our ability to identify these patients and to counsel them and their family members for subsequent disease risk, cancer surveillance, and therapeutic interventions. Herein, the leukemia susceptibility syndromes are divided into 3 groups: (1) those associated with an underlying inherited bone marrow failure syndrome, (2) disorders in which MDS precedes leukemia development, and (3) those with a risk primarily of leukemia. Although children are the focus of this review, it is important for clinicians to recognize that inherited susceptibility to cancer can present at any age, even in older adults; genetic counseling is essential and prompt referral to experts in each syndrome is strongly recommended.

scholarly journals Phosphorylation of the RB C-terminus regulates condensin II release from chromatin

2020 ◽  
pp. jbc.RA120.016511
Author(s):  
Seung J Kim ◽  
James I MacDonald ◽  
Frederick A. Dick
Keyword(s):  
Cell Cycle ◽  
Genome Stability ◽  
Cell Cycle Control ◽  
Cell Receptor ◽  
Receptor Activation ◽  
Biologically Relevant ◽  
C Terminus ◽  
Independent Functions ◽  
Phosphorylation Event ◽  
Rb Phosphorylation

The retinoblastoma tumour suppressor protein (RB) plays an important role in biological processes such as cell cycle control, DNA damage repair, epigenetic regulation, and genome stability. The canonical model of RB regulation is that cyclin-CDKs phosphorylate, and render RB inactive in late G1/S, promoting entry into S phase. Recently, mono-phosphorylated RB species were described to have distinct cell-cycle independent functions, suggesting that a phosphorylation code dictates diversity of RB function. However, a biologically relevant, functional role of RB phosphorylation at non-CDK sites has remained elusive. Here, we investigated S838/T841 dual phosphorylation, its upstream stimulus, and downstream functional output.  We found that mimicking T-cell receptor activation in Jurkat leukemia cells induced sequential activation of downstream kinases including p38 MAPK, and RB S838/T841 phosphorylation.  This signaling pathway disrupts RB and condensin II interaction with chromatin.  Using cells expressing a WT or S838A/T841A mutant RB fragment, we present evidence that deficiency for this phosphorylation event prevents condensin II release from chromatin.

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