scholarly journals An Update on the Role of Ubiquitination in Melanoma Development and Therapies

2021 ◽  
Vol 10 (5) ◽  
pp. 1133
Author(s):  
Frédéric Soysouvanh ◽  
Serena Giuliano ◽  
Nadia Habel ◽  
Najla El-Hachem ◽  
Céline Pisibon ◽  
...  
Keyword(s):  
Patient Outcomes ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Biological Processes ◽  
Large Array ◽  
Skin Cancers ◽  
Melanoma Patients ◽  
Ubiquitination System ◽  
Pleiotropic Functions

The ubiquitination system plays a critical role in regulation of large array of biological processes and its alteration has been involved in the pathogenesis of cancers, among them cutaneous melanoma, which is responsible for the most deaths from skin cancers. Over the last decades, targeted therapies and immunotherapies became the standard therapeutic strategies for advanced melanomas. However, despite these breakthroughs, the prognosis of metastatic melanoma patients remains unoptimistic, mainly due to intrinsic or acquired resistances. Many avenues of research have been investigated to find new therapeutic targets for improving patient outcomes. Because of the pleiotropic functions of ubiquitination, and because each step of ubiquitination is amenable to pharmacological targeting, much attention has been paid to the role of this process in melanoma development and resistance to therapies. In this review, we summarize the latest data on ubiquitination and discuss the possible impacts on melanoma treatments.

scholarly journals The 3’UTR of the orb2 gene encoding the Drosophila CPEB translation factor plays a critical role in spermatogenesis

2020 ◽  
Author(s):  
Rudolf A. Gilmutdinov ◽  
Eugene N. Kozlov ◽  
Ludmila V. Olenina ◽  
Alexei A. Kotov ◽  
Justinn Barr ◽  
...  
Keyword(s):  
Deletion Mutant ◽  
Critical Role ◽  
Self Regulation ◽  
Biological Processes ◽  
Apparent Effect ◽  
Gene Encoding ◽  
Cytoplasmic Polyadenylation ◽  
Polarized Cells ◽  
Biological Context

AbstractCPEB proteins are conserved translation regulators involved in multiple biological processes. One of these proteins in Drosophila, Orb2, is a principal player in spermatogenesis. It is required for meiosis and spermatid differentiation. During the later process orb2 mRNAs and proteins are localized within the developing spermatid. To evaluate the role of orb2 mRNA 3’UTR in spermatogenesis, we used the CRISPR/Cas9 system to generate a deletion of the orb2 3’UTR, orb2R. This deletion disrupts the process of spermatid differentiation, but has no apparent effect on meiosis. While this deletion appears to destabilize the orb2 mRNA and reduce the levels of Orb2 protein, this is not the primary cause of the differentiation defects. Instead, differentiation appears to be disrupted because orb2 mRNAs and proteins are not properly localized within the differentiating spermatids. Other transcripts and proteins involved in spermatogenesis are also mislocalized in orb2R spermatids.Author summaryThe conserved family of cytoplasmic polyadenylation element binding (CPEB) proteins can activate or repress translation of target mRNAs, depending on the specific biological context, through interaction with special cytoplasmic polyadenylation element (CPE) sequences. These proteins function mainly in highly polarized cells. Orb2, one of the two Drosophila melanogaster CPEB proteins, is predominantly expressed in the testes and is crucial for spermatogenesis. The 3’UTR of orb2 transcript contains multiple CPE-like motifs, which is indicative of orb2 self-regulation. We have generated a deletion that removes the greater portion of 3’UTR. While this deletion causes a reduction in the levels of orb2 mRNA and the protein, this does not appear to be responsible for the defects in spermatogenesis observed in the deletion mutant. Instead, it is the mislocalization of the mRNA and protein in the developing spermatids.

scholarly journals The Role of WAVE2 Signaling in Cancer

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1217
Author(s):  
Priyanka Shailendra Rana ◽  
Akram Alkrekshi ◽  
Wei Wang ◽  
Vesna Markovic ◽  
Khalid Sossey-Alaoui
Keyword(s):  
Actin Cytoskeleton ◽  
Cancer Cell ◽  
Cell Invasion ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Small Gtpases ◽  
Cancer Cell Invasion ◽  
Invasion And Metastasis ◽  
Regulatory Complex

The Wiskott–Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE)—WAVE1, WAVE2 and WAVE3 regulate rapid reorganization of cortical actin filaments and have been shown to form a key link between small GTPases and the actin cytoskeleton. Upon receiving upstream signals from Rho-family GTPases, the WASP and WAVE family proteins play a significant role in polymerization of actin cytoskeleton through activation of actin-related protein 2/3 complex (Arp2/3). The Arp2/3 complex, once activated, forms actin-based membrane protrusions essential for cell migration and cancer cell invasion. Thus, by activation of Arp2/3 complex, the WAVE and WASP family proteins, as part of the WAVE regulatory complex (WRC), have been shown to play a critical role in cancer cell invasion and metastasis, drawing significant research interest over recent years. Several studies have highlighted the potential for targeting the genes encoding either part of or a complete protein from the WASP/WAVE family as therapeutic strategies for preventing the invasion and metastasis of cancer cells. WAVE2 is well documented to be associated with the pathogenesis of several human cancers, including lung, liver, pancreatic, prostate, colorectal and breast cancer, as well as other hematologic malignancies. This review focuses mainly on the role of WAVE2 in the development, invasion and metastasis of different types of cancer. This review also summarizes the molecular mechanisms that regulate the activity of WAVE2, as well as those oncogenic pathways that are regulated by WAVE2 to promote the cancer phenotype. Finally, we discuss potential therapeutic strategies that target WAVE2 or the WAVE regulatory complex, aimed at preventing or inhibiting cancer invasion and metastasis.

scholarly journals CUL4A ubiquitin ligase: a promising drug target for cancer and other human diseases

Open Biology ◽  
2014 ◽  
Vol 4 (2) ◽  
pp. 130217 ◽  
Author(s):  
Puneet Sharma ◽  
Alo Nag
Keyword(s):  
Ubiquitin Ligase ◽  
Drug Target ◽  
Critical Role ◽  
Cellular Transformation ◽  
Biological Processes ◽  
Molecular Architecture ◽  
The Past ◽  
Cullin 4A ◽  
Broad Overview

The ability of cullin 4A (CUL4A), a scaffold protein, to recruit a repertoire of substrate adaptors allows it to assemble into distinct E3 ligase complexes to mediate turnover of key regulatory proteins. In the past decade, a considerable wealth of information has been generated regarding its biology, regulation, assembly, molecular architecture and novel functions. Importantly, unravelling of its association with multiple tumours and modulation by viral proteins establishes it as one of the key proteins that may play an important role in cellular transformation. Considering the role of its substrate in regulating the cell cycle and maintenance of genomic stability, understanding the detailed aspects of these processes will have significant consequences for the treatment of cancer and related diseases. This review is an effort to provide a broad overview of this multifaceted ubiquitin ligase and addresses its critical role in regulation of important biological processes. More importantly, its tremendous potential to be exploited for therapeutic purposes has been discussed.

scholarly journals Molecular characterization and clinical relevance of m6A regulators across 33 cancer types

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Yongsheng Li ◽  
Jun Xiao ◽  
Jing Bai ◽  
Yi Tian ◽  
Yinwei Qu ◽  
...  
Keyword(s):  
Clinical Relevance ◽  
Critical Role ◽  
Genetic Alterations ◽  
Biological Processes ◽  
Valuable Resource ◽  
Multiple Cancer ◽  
Molecular Alterations ◽  
Prognostic Stratification ◽  
Cancer Types

Abstract The methylation of N6 adenosine (m6A) plays a critical role in diverse biological processes. However, knowledge regarding the reconstitution of m6A across cancer types is still lacking. Here, we systematically analyzed the molecular alterations and clinical relevance of m6A regulators across > 10,000 subjects representing 33 cancer types. We found that there are widespread genetic alterations to m6A regulators, and that their expression levels are significantly correlated with the activity of cancer hallmark-related pathways. Moreover, m6A regulators were found to be potentially useful for prognostic stratification, and we identified IGF2BP3 as a potential oncogene across multiple cancer types. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the role of m6A regulators in cancer.

Analysis of the intricate relationship between chronic inflammation and cancer

2015 ◽  
Vol 468 (1) ◽  
pp. 1-15 ◽  
Author(s):  
Edna Zhi Pei Chai ◽  
Kodappully Sivaraman Siveen ◽  
Muthu K. Shanmugam ◽  
Frank Arfuso ◽  
Gautam Sethi
Keyword(s):  
Chronic Inflammation ◽  
Immune Cells ◽  
Patient Management ◽  
Critical Role ◽  
Tumour Microenvironment ◽  
Therapeutic Strategies ◽  
Exponential Rate ◽  
Hereditary Factors ◽  
Tumour Initiation

Deregulated inflammatory response plays a pivotal role in the initiation, development and progression of tumours. Potential molecular mechanism(s) that drive the establishment of an inflammatory-tumour microenvironment is not entirely understood owing to the complex cross-talk between pro-inflammatory and tumorigenic mediators such as cytokines, chemokines, oncogenes, enzymes, transcription factors and immune cells. These molecular mediators are critical linchpins between inflammation and cancer, and their activation and/or deactivation are influenced by both extrinsic (i.e. environmental and lifestyle) and intrinsic (i.e. hereditary) factors. At present, the research pertaining to inflammation-associated cancers is accumulating at an exponential rate. Interest stems from hope that new therapeutic strategies against molecular mediators can be identified to assist in cancer treatment and patient management. The present review outlines the various molecular and cellular inflammatory mediators responsible for tumour initiation, progression and development, and discusses the critical role of chronic inflammation in tumorigenesis.

scholarly journals Critical role of interferons in gastrointestinal injury repair

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Constance McElrath ◽  
Vanessa Espinosa ◽  
Jian-Da Lin ◽  
Jianya Peng ◽  
Raghavendra Sridhar ◽  
...  
Keyword(s):  
Critical Role ◽  
Mucosal Healing ◽  
Type I ◽  
Acute Colitis ◽  
Colonic Injury ◽  
Epithelial Regeneration ◽  
Complex Interactions ◽  
Pleiotropic Functions ◽  
Deficient Mice

AbstractThe etiology of ulcerative colitis is poorly understood and is likely to involve perturbation of the complex interactions between the mucosal immune system and the commensal bacteria of the gut, with cytokines acting as important cross-regulators. Here we use IFN receptor-deficient mice in a dextran sulfate sodium (DSS) model of acute intestinal injury to study the contributions of type I and III interferons (IFN) to the initiation, progression and resolution of acute colitis. We find that mice lacking both types of IFN receptors exhibit enhanced barrier destruction, extensive loss of goblet cells and diminished proliferation of epithelial cells in the colon following DSS-induced damage. Impaired mucosal healing in double IFN receptor-deficient mice is driven by decreased amphiregulin expression, which IFN signaling can up-regulate in either the epithelial or hematopoietic compartment. Together, these data underscore the pleiotropic functions of IFNs and demonstrate that these critical antiviral cytokines also support epithelial regeneration following acute colonic injury.

scholarly journals Mining the Gut Microbiota for Microbial-Based Therapeutic Strategies in Cancer Immunotherapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Bolei Li ◽  
Tao Gong ◽  
Yu Hao ◽  
Xuedong Zhou ◽  
Lei Cheng
Keyword(s):  
Immune System ◽  
Gut Microbiota ◽  
Cancer Immunotherapy ◽  
Critical Role ◽  
Therapeutic Strategies ◽  
Host Immune System ◽  
The Past ◽  
Promising Strategy

The past two decades witnessed a revolution in our understanding of host–microbiota interactions that led to the concept of the super-organism consisting of a eukaryotic part and a prokaryotic part. Owing to the critical role of gut microbiota in modulating the host immune system, it is not beyond all expectations that more and more evidence indicated that the shift of gut microbiota influenced responses to numerous forms of cancer immunotherapy. Therapy targeting gut microbiota is becoming a promising strategy to improve cancer immunotherapy. In this review, we discuss the role of the gut microbiota in response to cancer immunotherapy, the mechanisms that the gut microbiota influences cancer immunotherapy, and therapeutic strategies targeting gut microbiota to improve cancer immunotherapy.

scholarly journals Cleavage and activation of LIM kinase 1 as a novel mechanism for calpain 2-mediated regulation of nuclear dynamics

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
L. Rodríguez-Fernández ◽  
S. Company ◽  
R. Zaragozá ◽  
J. R. Viña ◽  
E. R. García-Trevijano
Keyword(s):  
Critical Role ◽  
Nuclear Interaction ◽  
Cell Periphery ◽  
Cell Nuclei ◽  
Nuclear Dynamics ◽  
Lim Kinase ◽  
Lim Kinase 1 ◽  
Calpain 2 ◽  
Pleiotropic Functions

AbstractCalpain-2 (CAPN2) is a processing enzyme ubiquitously expressed in mammalian tissues whose pleiotropic functions depend on the role played by its cleaved-products. Nuclear interaction networks, crucial for a number of molecular processes, could be modified by CAPN2 activity. However, CAPN2 functions in cell nucleus are poorly understood. To unveil CAPN2 functions in this compartment, the result of CAPN2-mediated interactions in cell nuclei was studied in breast cancer cell (BCC) lines. CAPN2 abundance was found to be determinant for its nucleolar localization during interphase. Those CAPN2-dependent components of nucleolar proteome, including the actin-severing protein cofilin-1 (CFL1), were identified by proteomic approaches. CAPN2 binding, cleavage and activation of LIM Kinase-1 (LIMK1), followed by CFL1 phosphorylation was studied. Upon CAPN2-depletion, full-length LIMK1 levels increased and CFL1/LIMK1 binding was inhibited. In addition, LIMK1 accumulated at the cell periphery and perinucleolar region and, the mitosis-specific increase of CFL1 phosphorylation and localization was altered, leading to aberrant mitosis and cell multinucleation. These findings uncover a mechanism for the role of CAPN2 during mitosis, unveil the critical role of CAPN2 in the interactions among nuclear components and, identifying LIMK1 as a new CAPN2-target, provide a novel mechanism for LIMK1 activation. CFL1 is crucial for cytoskeleton remodeling and mitosis, but also for the maintenance of nuclear structure, the movement of chromosomes and the modulation of transcription frequently altered in cancer cells. Consequently, the role of CAPN2 in the nuclear compartment might be extended to other actin-associated biological and pathological processes.

scholarly journals p53 Family: Role of Protein Isoforms in Human Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-19 ◽  
Author(s):  
Jinxiong Wei ◽  
Elena Zaika ◽  
Alexander Zaika
Keyword(s):  
Human Cancer ◽  
Critical Role ◽  
Protein Isoforms ◽  
Biological Processes ◽  
Family Role ◽  
P53 Family ◽  
Curative Therapy ◽  
Isoform Diversity ◽  
Alternative Mrna Splicing

TP53,TP63, andTP73genes comprise the p53 family. Each gene produces protein isoforms through multiple mechanisms including extensive alternative mRNA splicing. Accumulating evidence shows that these isoforms play a critical role in the regulation of many biological processes in normal cells. Their abnormal expression contributes to tumorigenesis and has a profound effect on tumor response to curative therapy. This paper is an overview of isoform diversity in the p53 family and its role in cancer.

scholarly journals The 3'UTR of the orb2 gene encoding the Drosophila CPEB translation factor plays a critical role in spermatogenesis

Development ◽  
2021 ◽  
Author(s):  
Rudolf A. Gilmutdinov ◽  
Eugene N. Kozlov ◽  
Konstantin V. Yakovlev ◽  
Ludmila V. Olenina ◽  
Alexei A. Kotov ◽  
...  
Keyword(s):  
Critical Role ◽  
Biological Processes ◽  
Apparent Effect ◽  
Gene Encoding ◽  
Translation Factor ◽  
Initial Polarization

CPEB proteins are conserved translation regulators involved in multiple biological processes. One of these proteins in Drosophila, Orb2, is a principal player in spermatogenesis. It is required for meiosis and spermatid differentiation. During the later process orb2 mRNAs and proteins are localized within the developing spermatid. To evaluate the role of orb2 mRNA 3'UTR in spermatogenesis, we used the CRISPR/Cas9 system to generate a deletion of the orb2 3'UTR, orb2R. This deletion disrupts the process of spermatid differentiation but has no apparent effect on meiosis. Differentiation abnormalities include defects in the initial polarization of the 64-cell spermatid cysts, mislocalization of mRNAs and proteins in the elongating spermatid tails, altered morphology of the elongating spermatid tails, and defects in the assembly of the individualization complex. These disruptions in differentiation appear to arise because orb2 mRNAs and proteins are not properly localized within the 64-cell spermatid cyst.

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