scholarly journals Secretory Autophagy Forges a Therapy Resistant Microenvironment in Melanoma

Cancers ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 234
Author(s):  
Silvina Odete Bustos ◽  
Nathalia Leal Santos ◽  
Roger Chammas ◽  
Luciana Nogueira de Sousa Andrade
Keyword(s):  
Cell Fate ◽  
Clinical Findings ◽  
Multiple Roles ◽  
Tumor Resistance ◽  
Complex Environment ◽  
Mutational Burden ◽  
Exosome Biogenesis ◽  
Cell Progression ◽  
Large Heterogeneity ◽  
Secretory Autophagy

Melanoma is the most aggressive skin cancer characterized by high mutational burden and large heterogeneity. Cancer cells are surrounded by a complex environment, critical to tumor establishment and progression. Thus, tumor-associated stromal components can sustain tumor demands or impair cancer cell progression. One way to manage such processes is through the regulation of autophagy, both in stromal and tumor cells. Autophagy is a catabolic mechanism that provides nutrients and energy, and it eliminates damaged organelles by degradation and recycling of cellular elements. Besides this primary function, autophagy plays multiple roles in the tumor microenvironment capable of affecting cell fate. Evidence demonstrates the existence of novel branches in the autophagy system related to cytoplasmic constituent’s secretion. Hence, autophagy-dependent secretion assembles a tangled network of signaling that potentially contributes to metabolism reprogramming, immune regulation, and tumor progression. Here, we summarize the current awareness regarding secretory autophagy and the intersection with exosome biogenesis and release in melanoma and their role in tumor resistance. In addition, we present and discuss data from public databases concerning autophagy and exosome-related genes as important mediators of melanoma behavior. Finally, we will present the main challenges in the field and strategies to translate most of the pre-clinical findings to clinical practice.

Oestrogens as apoptosis regulators in mammalian testis: angels or devils?

2015 ◽  
Vol 17 ◽  
Author(s):  
Sara Correia ◽  
Henrique J. Cardoso ◽  
José E. Cavaco ◽  
Sílvia Socorro
Keyword(s):  
Cell Death ◽  
Germ Cell ◽  
Cell Survival ◽  
Cell Fate ◽  
Germ Line ◽  
Clinical Findings ◽  
Molecular Events ◽  
Mammalian Testis ◽  
Induced Apoptosis ◽  
Available Information

In the mammalian testis, spermatogenesis is a highly coordinated process of germ cell development, which ends with the release of ‘mature’ spermatozoa. The fine regulation of spermatogenesis is strictly dependent on sex steroid hormones, which orchestrate the cellular and molecular events underlying normal development of germ cells. Sex steroids actions also rely on the control of germ cell survival, and the programmed cell death by apoptosis has been indicated as a critical process in regulating the size and quality of the germ line. Recently, oestrogens have emerged as important regulators of germ cell fate. However, the beneficial or detrimental effects of oestrogens in spermatogenesis are controversial, with independent reports arguing for their role as cell survival factors or as apoptosis-inducers. The dual behaviour of oestrogens, shifting from ‘angels to devils’ is supported by the clinical findings of increased oestrogens levels in serum and intratesticular milieu of idiopathic infertile men. This review aims to discuss the available information concerning the role of oestrogens in the control of germ cell death and summarises the signalling mechanisms driven oestrogen-induced apoptosis. The present data represent a valuable basis for the clinical management of hyperoestrogenism-related infertility and provide a rationale for the use of oestrogen-target therapies in male infertility.

scholarly journals Differences and similarities between cancer and somatic stem cells: therapeutic implications

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Fiorella Rossi ◽  
Hunter Noren ◽  
Richard Jove ◽  
Vladimir Beljanski ◽  
Karl-Henrik Grinnemo
Keyword(s):  
Stem Cells ◽  
Cell Fate ◽  
Cancer Survival ◽  
Rapid Progression ◽  
Tumor Resistance ◽  
Somatic Stem Cells ◽  
Cancer Treatments ◽  
Tumor Mass ◽  
Therapeutic Implications ◽  
The Brain

AbstractOver the last decades, the cancer survival rate has increased due to personalized therapies, the discovery of targeted therapeutics and novel biological agents, and the application of palliative treatments. Despite these advances, tumor resistance to chemotherapy and radiation and rapid progression to metastatic disease are still seen in many patients. Evidence has shown that cancer stem cells (CSCs), a sub-population of cells that share many common characteristics with somatic stem cells (SSCs), contribute to this therapeutic failure. The most critical properties of CSCs are their self-renewal ability and their capacity for differentiation into heterogeneous populations of cancer cells. Although CSCs only constitute a low percentage of the total tumor mass, these cells can regrow the tumor mass on their own. Initially identified in leukemia, CSCs have subsequently been found in cancers of the breast, the colon, the pancreas, and the brain. Common genetic and phenotypic features found in both SSCs and CSCs, including upregulated signaling pathways such as Notch, Wnt, Hedgehog, and TGF-β. These pathways play fundamental roles in the development as well as in the control of cell survival and cell fate and are relevant to therapeutic targeting of CSCs. The differences in the expression of membrane proteins and exosome-delivered microRNAs between SSCs and CSCs are also important to specifically target the stem cells of the cancer. Further research efforts should be directed toward elucidation of the fundamental differences between SSCs and CSCs to improve existing therapies and generate new clinically relevant cancer treatments.

Glued participates in distinct microtubule-based activities in Drosophila eye development

Development ◽  
1997 ◽  
Vol 124 (8) ◽  
pp. 1497-1507 ◽  
Author(s):  
S.S. Fan ◽  
D.F. Ready
Keyword(s):  
Cell Fate ◽  
Eye Development ◽  
Cytoplasmic Dynein ◽  
Dominant Negative ◽  
Multiple Roles ◽  
Cell Fate Determination ◽  
Stage Of Development ◽  
Multiple Phenotypes ◽  
Drosophila Homolog ◽  
Distinct Features

A C-terminal truncation of Glued, the Drosophila homolog of the cytoplasmic dynein activating protein, dynactin, results in a severe and complex retinal phenotype, including a roughening of the facet array, malformation of the photosensitive rhabdomeres, and a general deficit and disorder of retinal cells. We have characterized the developmental phenotype in Glued1 and found defects in multiple stages of eye development, including mitosis, nuclear migration, cell fate determination, rhabdomere morphogenesis and cell death. Transgenic flies that express dominant negative Glued under heat-shock control reproduce distinct features of the original Glued1 phenotype depending on the stage of development. The multiple phenotypes effected by truncated Glued point to the multiple roles served by dynactin/dynein during eye development.

scholarly journals TP53 in Myelodysplastic Syndromes: Recent Biological and Clinical Findings

2020 ◽  
Vol 21 (10) ◽  
pp. 3432
Author(s):  
Cosimo Cumbo ◽  
Giuseppina Tota ◽  
Luisa Anelli ◽  
Antonella Zagaria ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Chromosomal Instability ◽  
Clonal Evolution ◽  
Clinical Findings ◽  
Therapeutic Approaches ◽  
New Therapeutic Approaches ◽  
Mutational Burden ◽  
Mutational Status ◽  
Allelic State ◽  
Tp53 Mutational Status

TP53 dysregulation plays a pivotal role in the molecular pathogenesis of myelodysplastic syndromes (MDS), identifying a subgroup of patients with peculiar features. In this review we report the recent biological and clinical findings of TP53-mutated MDS, focusing on the molecular pathways activation and on its impact on the cellular physiology. In MDS, TP53 mutational status is deeply associated with del(5q) syndrome and its dysregulation impacts on cell cycle, DNA repair and apoptosis inducing chromosomal instability and the clonal evolution of disease. TP53 defects influence adversely the MDS clinical outcome and the treatment response rate, thus new therapeutic approaches are being developed for these patients. TP53 allelic state characterization and the mutational burden evaluation can therefore predict prognosis and identify the subgroup of patients eligible for targeted therapy. For these reasons, in the era of precision medicine, the MDS diagnostic workup cannot do without the complete assessment of TP53 mutational profile.

scholarly journals Cell and molecular biology of Notch

2007 ◽  
Vol 194 (3) ◽  
pp. 459-474 ◽  
Author(s):  
Ulla-Maj Fiúza ◽  
Alfonso Martinez Arias
Keyword(s):  
Cell Fate ◽  
Cell Communication ◽  
Notch Signalling ◽  
Multiple Roles ◽  
Communication Process ◽  
Regulatory Mechanisms ◽  
Cell Populations ◽  
Notch Signalling Pathway ◽  
A Cell ◽  
Stem Cell Populations

Notch signalling is a cell–cell communication process, which allows the establishment of patterns of gene expression and differentiation, regulates binary cell fate choice and the maintenance of stem cell populations. So far, the data published has elucidated the main players in the Notch signalling pathway. However, its regulatory mechanisms are exhibiting an increasing complexity which could account for the multitude of roles it has during development and in adult organisms. In this review, we will describe the multiple roles of Notch and how various factors can regulate Notch signalling.

scholarly journals A Paradigm in Immunochemistry, Revealed by Monoclonal Antibodies to Spatially Distinct Epitopes on Syntenin-1

2019 ◽  
Vol 20 (23) ◽  
pp. 6035
Author(s):  
Johnson ◽  
Sorvina ◽  
Logan ◽  
Moore ◽  
Heatlie ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Membrane Trafficking ◽  
Early Stage ◽  
Amino Acid Level ◽  
Focal Adhesions ◽  
Adaptor Protein ◽  
Multiple Roles ◽  
Linear Sequence ◽  
Cancer Pathogenesis ◽  
Exosome Biogenesis

Syntenin-1 is an essential multi-functional adaptor protein, which has multiple roles in membrane trafficking and exosome biogenesis, as well as scaffolding interactions with either the actin cytoskeleton or focal adhesions. However, how this functional multiplicity relates to syntenin-1 distribution in different endosome compartments or other intracellular locations and its underlying involvement in cancer pathogenesis have yet to be fully defined. To help facilitate the investigation of syntenin-1 biology, we developed two specific monoclonal antibodies (Synt-2C6 and Synt-3A11) to spatially distinct linear sequence epitopes on syntenin-1, which were each designed to be unique at the six-amino acid level. These antibodies produced very different intracellular staining patterns, with Synt-2C6 detecting endosomes and Synt-3A11 producing a fibrillar staining pattern suggesting a cytoskeletal localisation. Treatment of cells with Nocodazole altered the intracellular localisation of Synt-3A11, which was consistent with the syntenin-1 protein interacting with microtubules. In prostate tissue biopsies, Synt-3A11 defined atrophy and early-stage prostate cancer, whereas Synt-2C6 only showed minimal interaction with atrophic tissue. This highlights a critical need for site-specific antibodies and a knowledge of their reactivity to define differential protein distributions, interactions and functions, which may differ between normal and malignant cells.

scholarly journals TRANSPARENT TESTA GLABRA1, a Key Regulator in Plants with Multiple Roles and Multiple Function Mechanisms

2020 ◽  
Vol 21 (14) ◽  
pp. 4881 ◽  
Author(s):  
Hainan Tian ◽  
Shucai Wang
Keyword(s):  
Transcription Factor ◽  
Cell Fate ◽  
Target Genes ◽  
Multiple Roles ◽  
26S Proteasome ◽  
Bhlh Transcription Factor ◽  
Transcription Activator ◽  
Downstream Target ◽  
Transparent Testa ◽  
Functional Mechanisms

TRANSPARENT TESTA GLABRA1 (TTG1) is a WD40 repeat protein. The phenotypes caused by loss-of-function of TTG1 were observed about half a century ago, but the TTG1 gene was identified only about twenty years ago. Since then, TTG1 has been found to be a plant-specific regulator with multiple roles and multiple functional mechanisms. TTG1 is involved in the regulation of cell fate determination, secondary metabolisms, accumulation of seed storage reserves, plant responses to biotic and abiotic stresses, and flowering time in plants. In some processes, TTG1 may directly or indirectly regulate the expression of downstream target genes via forming transcription activator complexes with R2R3 MYB and bHLH transcription factors. Whereas in other processes, TTG1 may function alone or interact with other proteins to regulate downstream target genes. On the other hand, the studies on the regulation of TTG1 are very limited. So far, only the B3-domain family transcription factor FUSCA3 (FUS3) has been found to regulate the expression of TTG1, phosphorylation of TTG1 affects its interaction with bHLH transcription factor TT2, and TTG1 proteins can be targeted for degradation by the 26S proteasome. Here, we provide an overview of TTG1, including the identification of TTG1, the functions of TTG1, the possible function mechanisms of TTG1, and the regulation of TTG1. We also proposed potential research directions that may shed new light on the regulation and functional mechanisms of TTG1 in plants.

scholarly journals The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Luisa Capalbo ◽  
Zuni I. Bassi ◽  
Marco Geymonat ◽  
Sofia Todesca ◽  
Liviu Copoiu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Interaction Network ◽  
Multiple Roles ◽  
Intercellular Bridge ◽  
Lumen Formation ◽  
Protein Protein Interaction ◽  
Daughter Cells ◽  
Tissue Organization ◽  
Protein Protein Interaction Network

Abstract The midbody is an organelle assembled at the intercellular bridge between the two daughter cells at the end of mitosis. It controls the final separation of the daughter cells and has been involved in cell fate, polarity, tissue organization, and cilium and lumen formation. Here, we report the characterization of the intricate midbody protein-protein interaction network (interactome), which identifies many previously unknown interactions and provides an extremely valuable resource for dissecting the multiple roles of the midbody. Initial analysis of this interactome revealed that PP1β-MYPT1 phosphatase regulates microtubule dynamics in late cytokinesis and de-phosphorylates the kinesin component MKLP1/KIF23 of the centralspindlin complex. This de-phosphorylation antagonizes Aurora B kinase to modify the functions and interactions of centralspindlin in late cytokinesis. Our findings expand the repertoire of PP1 functions during mitosis and indicate that spatiotemporal changes in the distribution of kinases and counteracting phosphatases finely tune the activity of cytokinesis proteins.

Cullin-5 plays multiple roles in cell fate specification and synapse formation duringDrosophila development

2005 ◽  
Vol 232 (3) ◽  
pp. 865-875 ◽  
Author(s):  
Champakali Ayyub ◽  
Anindya Sen ◽  
Foster Gonsalves ◽  
Kishan Badrinath ◽  
Poonam Bhandari ◽  
...  
Keyword(s):  
Cell Fate ◽  
Synapse Formation ◽  
Multiple Roles ◽  
Cell Fate Specification ◽  
Fate Specification ◽  
Cullin 5

scholarly journals The midbody interactome reveals new unexpected roles for PP1 phosphatases in cytokinesis

2019 ◽  
Author(s):  
Luisa Capalbo ◽  
Zuni I. Bassi ◽  
Marco Geymonat ◽  
Sofia Todesca ◽  
Liviu Copoiu ◽  
...  
Keyword(s):  
Cell Fate ◽  
Interaction Network ◽  
Multiple Roles ◽  
Lumen Formation ◽  
Protein Protein Interaction ◽  
Daughter Cells ◽  
Tissue Organization ◽  
Novel Interactions ◽  
Protein Protein Interaction Network

AbstractThe midbody is an organelle assembled at the intercellular bridge that connects the two daughter cells at the end of mitosis. It is composed of a multitude of proteins, organized in a precise and stereotyped pattern, that control the final separation of the daughter cells and prevent incorrect genome segregation. Furthermore, recent evidence indicates that the midbody is involved in many other important processes, including cell fate, pluripotency, apical-basal polarity, tissue organization, and cilium and lumen formation. Understanding the regulation and interactions of midbody proteins is therefore essential to unravel how this organelle executes its multiple functions. Here, we report the first experimentally-based characterization of the intricate midbody protein-protein interaction network (interactome), which identifies a plethora of novel interactions and provides an extremely valuable resource for dissecting the multiple roles of the midbody. Initial analysis of this interactome already revealed that PP1β-MYPT1 phosphatase regulates microtubule dynamics in late cytokinesis and de-phosphorylates the kinesin component MKLP1/KIF23 of the centralspindlin complex, a key cytokinesis regulator. This de-phosphorylation antagonizes Aurora B kinase in order to modify the functions of centralspindlin and its interactions in late cytokinesis. Our findings expand the repertoire of PP1 functions during mitosis and indicate that spatiotemporal changes in the distribution of kinases and counteracting phosphatases finely tune the activity of cytokinesis proteins.

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