A Systematic Screen for Dominant Second-Site Modifiers of Merlin/NF2 Phenotypes Reveals an Interaction With blistered/DSRF and scribbler

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 667-679
Author(s):  
Dennis R LaJeunesse ◽  
Brooke M McCartney ◽  
Richard G Fehon
Keyword(s):  
Human Tumor ◽  
Suppressor Gene ◽  
Dominant Negative ◽  
Loss Of Function ◽  
Genetic Screens ◽  
Cellular Functions ◽  
Cell Proliferation And Differentiation ◽  
Epithelial Development ◽  
Proliferation And Differentiation ◽  
Neuronal Tissues

Abstract Merlin, the Drosophila homologue of the human tumor suppressor gene Neurofibromatosis 2 (NF2), is required for the regulation of cell proliferation and differentiation. To better understand the cellular functions of the NF2 gene product, Merlin, recent work has concentrated on identifying proteins with which it interacts either physically or functionally. In this article, we describe genetic screens designed to isolate second-site modifiers of Merlin phenotypes from which we have identified five multiallelic complementation groups that modify both loss-of-function and dominant-negative Merlin phenotypes. Three of these groups, Group IIa/scribbler (also known as brakeless), Group IIc/blistered, and Group IId/net, are known genes, while two appear to be novel. In addition, two genes, Group IIa/scribbler and Group IIc/blistered, alter Merlin subcellular localization in epithelial and neuronal tissues, suggesting that they regulate Merlin trafficking or function. Furthermore, we show that mutations in scribbler and blistered display second-site noncomplementation with one another. These results suggest that Merlin, blistered, and scribbler function together in a common pathway to regulate Drosophila wing epithelial development.

scholarly journals Analysis of ERK3 intracellular localization: dynamic distribution during mitosis and apoptosis

2015 ◽  
Vol 59 (4) ◽  
Author(s):  
F. Aredia ◽  
M. Malatesta ◽  
P. Veneroni ◽  
M.G. Bottone
Keyword(s):  
Cell Cycle ◽  
Intracellular Localization ◽  
Human Tumor ◽  
Mrna Splicing ◽  
Double Immunofluorescence ◽  
Dynamic Distribution ◽  
Cell Proliferation And Differentiation ◽  
Extracellular Signal ◽  
Proliferation And Differentiation ◽  
Cycle Dependent

<p>Extracellular signal-regulated kinases (ERK) 1, 2 and 3 are involved in cell proliferation and differentiation, and apoptosis; although ERK1/2 have been widely studied, limited knowledge on ERK3 is available. The present work aimed at investigating ERK3 distribution during cell cycle and apoptosis in human tumor HeLa cells. The analysis performed by double immunofluorescence and immunoelectron microscopy experiments revealed that during interphase ERK3 is mainly resident in the nucleoplasm in association with ribonuclear proteins involved in early pre-mRNA splicing, it undergoes cell cycle-dependent redistribution and, during apoptosis, it remains in the nucleus in the form of massive nuclear aggregates, then moves to the cytoplasm and is finally extruded.</p>

scholarly journals Non-apoptotic caspase activation sustains ovarian somatic stem cell functions by modulating Hedgehog-signalling and autophagy

2019 ◽  
Author(s):  
Alessia Galasso ◽  
Daria Iakovleva ◽  
Luis Alberto Baena-Lopez
Keyword(s):  
Stem Cell ◽  
Fine Tuning ◽  
Caspase Activation ◽  
Cellular Functions ◽  
Hedgehog Signalling ◽  
Cell Functions ◽  
Metabolic Defects ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Moderate Stress

ABSTRACTThere is increasing evidence associating the activity of caspases with the regulation of basic cellular functions beyond apoptosis. Accordingly, the dysregulation of these novel non-apoptotic functions often sits at the origin of neurological disorders, metabolic defects, autoimmunity, and cancer. However, the molecular interplay between caspases and the signalling networks active in non-apoptotic cellular scenarios remains largely unknown. Our work show that non-apoptotic caspase activation is critical to modulate Hedgehog-signalling and autophagy in ovarian somatic cells from both Drosophila and humans under moderate stress. We also demonstrate that these novel caspase functions are key to sustain stem cell proliferation and differentiation without inducing apoptosis. Finally, we molecularly link these caspase-dependent effects to the fine-tuning of the Hedgehog-receptor, Patched. Together, these findings confer a pro-survival role to the caspases, as opposed to the widely held apoptotic function assigned to these enzymes.

Cancer genetics: mouse models of intestinal cancer

2007 ◽  
Vol 35 (5) ◽  
pp. 1338-1341 ◽  
Author(s):  
A.R. Clarke
Keyword(s):  
Target Genes ◽  
Cancer Genetics ◽  
Suppressor Gene ◽  
Tumour Suppressor Gene ◽  
Loss Of Function ◽  
Cellular Functions ◽  
Control Of Gene Expression ◽  
Approaches To Study ◽  
Temporal And Spatial

The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181–193; Shaw and Clarke (2007) DNA Repair 6, 1403–1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519–531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.

The zebrafish udu gene encodes a novel nuclear factor and is essential for primitive erythroid cell development

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 99-106 ◽  
Author(s):  
Yanmei Liu ◽  
Linsen Du ◽  
Motomi Osato ◽  
Eng Hui Teo ◽  
Feng Qian ◽  
...  
Keyword(s):  
Positional Cloning ◽  
Erythroid Cell ◽  
Nuclear Factor ◽  
Loss Of Function ◽  
Cell Proliferation And Differentiation ◽  
Complex Process ◽  
Proliferation And Differentiation ◽  
Ugly Duckling ◽  
A Cell ◽  
Α Helix

Hematopoiesis is a complex process which gives rise to all blood lineages in the course of an organism's lifespan. However, the underlying molecular mechanism governing this process is not fully understood. Here we report the isolation and detailed study of a newly identified zebrafish ugly duckling (Udu) mutant allele, Udusq1. We show that loss-of-function mutation in the udu gene disrupts primitive erythroid cell proliferation and differentiation in a cell-autonomous manner, resulting in red blood cell (RBC) hypoplasia. Positional cloning reveals that the Udu gene encodes a novel factor that contains 2 paired amphipathic α-helix–like (PAH-L) repeats and a putative SANT-L (SW13, ADA2, N-Cor, and TFIIIB–like) domain. We further show that the Udu protein is predominantly localized in the nucleus and deletion of the putative SANT-L domain abolishes its function. Our study indicates that the Udu protein is very likely to function as a transcription modulator essential for the proliferation and differentiation of erythroid lineage.

scholarly journals Targeting cholesterol homeostasis in hematopoietic malignancies

Blood ◽  
2021 ◽  
Author(s):  
Andrea Brendolan ◽  
Vincenzo Russo
Keyword(s):  
Cholesterol Homeostasis ◽  
Cell Integrity ◽  
Cellular Functions ◽  
Hematopoietic Malignancies ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
X Receptors

Cholesterol is a vital lipid for cellular functions. It is necessary for membrane biogenesis, cell proliferation and differentiation. In addition to maintaining cell integrity and permeability, increasing evidence indicates a strict link between cholesterol homeostasis, inflammation and haematological tumors. This makes cholesterol homeostasis an optimal therapeutic target for hematopoietic malignancies. Manipulating cholesterol homeostasis either interfering with its synthesis or activating the reverse cholesterol transport via the engagement of liver X receptors (LXRs), affects the integrity of tumor cells both in vitro and in vivo. Cholesterol homeostasis has also been manipulated to restore antitumor immune responses in preclinical models. These observations have prompted clinical trials in acute myeloid leukemia (AML) to test the combination of chemotherapy with drugs interfering with cholesterol synthesis, i.e. statins. We review the role of cholesterol homeostasis in hematopoietic malignancies, as well as in cells of the tumor microenvironment, and discuss the potential use of lipid modulators for therapeutic purposes.

The neurofibromatosis-2 homologue, Merlin, and the tumor suppressor expanded function together in Drosophila to regulate cell proliferation and differentiation

Development ◽  
2000 ◽  
Vol 127 (6) ◽  
pp. 1315-1324 ◽  
Author(s):  
B.M. McCartney ◽  
R.M. Kulikauskas ◽  
D.R. LaJeunesse ◽  
R.G. Fehon
Keyword(s):  
Cell Proliferation ◽  
Tumor Suppressor ◽  
Genetic Interaction ◽  
Suppressor Gene ◽  
Loss Of Function ◽  
Cortical Actin ◽  
Neurofibromatosis 2 ◽  
Protein 4.1 ◽  
Proliferation And Differentiation ◽  
Affected Tissue

Neurofibromatosis-2 is an inherited disorder characterized by the development of benign schwannomas and other Schwann-cell-derived tumors associated with the central nervous system. The Neurofibromatosis-2 tumor suppressor gene encodes Merlin, a member of the Protein 4.1 superfamily most closely related to Ezrin, Radixin and Moesin. This discovery suggested a novel function for Protein 4.1 family members in the regulation of cell proliferation; proteins in this family were previously thought to function primarily to link transmembrane proteins to underlying cortical actin. To understand the basic cellular functions of Merlin, we are investigating a Drosophila Neurofibromatosis-2 homologue, Merlin. Loss of Merlin function in Drosophila results in hyperplasia of the affected tissue without significant disruptions in differentiation. Similar phenotypes have been observed for mutations in another Protein 4.1 superfamily member in Drosophila, expanded. Because of the phenotypic and structural similarities between Merlin and expanded, we asked whether Merlin and Expanded function together to regulate cell proliferation. In this study, we demonstrate that recessive loss of function of either Merlin or expanded can dominantly enhance the phenotypes associated with mutations in the other. Consistent with this genetic interaction, we determined that Merlin and Expanded colocalize in Drosophila tissues and cells, and physically interact through a conserved N-terminal region of Expanded, characteristic of the Protein 4.1 family, and the C-terminal domain of Merlin. Loss of function of both Merlin and expanded in clones revealed that these proteins function to regulate differentiation in addition to proliferation in Drosophila. Further genetic analyses suggest a role for Merlin and Expanded specifically in Decapentaplegic-mediated differentiation events. These results indicate that Merlin and Expanded function together to regulate proliferation and differentiation, and have implications for understanding the functions of other Protein 4.1 superfamily members.

scholarly journals Investigating the Role of VDR and Megalin in Semi-Selectivity of Side-Chain Modified 19-nor Analogs of Vitamin D

2019 ◽  
Vol 20 (17) ◽  
pp. 4183 ◽  
Author(s):  
Klaudia Berkowska ◽  
Aoife Corcoran ◽  
Małgorzata Grudzień ◽  
Agnieszka Jakuszak ◽  
Michał Chodyński ◽  
...  
Keyword(s):  
Vitamin D ◽  
Calcium Homeostasis ◽  
Minor Effect ◽  
Cellular Functions ◽  
Antitumor Effects ◽  
Dihydroxyvitamin D3 ◽  
Knock Out ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
A Minor

1,25-dihydroxyvitamin D3 (1,25D3) is implicated in many cellular functions, including cell proliferation and differentiation, thus exerting potential antitumor effects. A major limitation for therapeutic use of 1,25D3 are potent calcemic activities. Therefore, synthetic analogs of 1,25D3 for use in anticancer therapy should retain cell differentiating potential, with calcemic activity being reduced. To obtain this goal, the analogs should effectively activate transcription of genes responsible for cell differentiation, leaving the genes responsible for calcium homeostasis less active. In order to better understand this phenomenon, we selected a series of structurally related 19-nor analogs of 1,25D (PRI-5100, PRI-5101, PRI-5105, and PRI-5106) and tested their activities in blood cells and in cells connected to calcium homeostasis. Affinities of analogs to recombinant vitamin D receptor (VDR) protein were not correlated to their pro-differentiating activities. Moreover, the pattern of transcriptional activities of the analogs was different in cell lines originating from various vitamin D-responsive tissues. We thus hypothesized that receptors which participate in transport of the analogs to the cells might contribute to the observed differences. In order to study this hypothesis, we produced renal cells with knock-out of the megalin gene. Our results indicate that megalin has a minor effect on semi-selective activities of vitamin D analogs.

scholarly journals Targeting of SET/I2PP2A oncoprotein inhibits Gli1 transcription revealing a new modulator of Hedgehog signaling

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Iliana Serifi ◽  
Simoni Besta ◽  
Zoe Karetsou ◽  
Panagiota Giardoglou ◽  
Dimitris Beis ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Hedgehog Signaling ◽  
Luciferase Reporter ◽  
Loss Of Function ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Patterning Defect ◽  
Hh Signaling ◽  
Expression In Mammalian Cells

AbstractThe Hedgehog (Hh)/Gli signaling pathway controls cell proliferation and differentiation, is critical for the development of nearly every tissue and organ in vertebrates and is also involved in tumorigenesis. In this study, we characterize the oncoprotein SET/I2PP2A as a novel regulator of Hh signaling. Our previous work has shown that the zebrafish homologs of SET are expressed during early development and localized in the ciliated organs. In the present work, we show that CRISPR/Cas9-mediated knockdown of setb gene in zebrafish embryos resulted in cyclopia, a characteristic patterning defect previously reported in Hh mutants. Consistent with these findings, targeting setb gene using CRISPR/Cas9 or a setb morpholino, reduced Gli1-dependent mCherry expression in the Hedgehog reporter zebrafish line Tg(12xGliBS:mCherry-NLS). Likewise, SET loss of function by means of pharmacological inhibition and gene knockdown prevented the increase of Gli1 expression in mammalian cells in vitro. Conversely, overexpression of SET resulted in an increase of the expression of a Gli-dependent luciferase reporter, an effect likely attributable to the relief of the Sufu-mediated inhibition of Gli1. Collectively, our data support the involvement of SET in Gli1-mediated transcription and suggest the oncoprotein SET/I2PP2A as a new modulator of Hedgehog signaling.

scholarly journals p53, A Victim of the Prion Fashion

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 269
Author(s):  
Olivier Billant ◽  
Gaëlle Friocourt ◽  
Pierre Roux ◽  
Cécile Voisset
Keyword(s):  
Target Genes ◽  
Current Knowledge ◽  
Tumor Development ◽  
Suppressor Gene ◽  
Dominant Negative ◽  
Mutant P53 ◽  
P53 Mutations ◽  
Cellular Functions ◽  
Amyloid Aggregates ◽  
Functional Consequences

Identified in the late 1970s as an oncogene, a driving force leading to tumor development, p53 turned out to be a key tumor suppressor gene. Now p53 is considered a master gene regulating the transcription of over 3000 target genes and controlling a remarkable number of cellular functions. The elevated prevalence of p53 mutations in human cancers has led to a recurring questioning about the roles of mutant p53 proteins and their functional consequences. Both mutants and isoforms of p53 have been attributed dominant-negative and gain of function properties among which is the ability to form amyloid aggregates and behave in a prion-like manner. This report challenges the ongoing “prion p53” hypothesis by reviewing evidence of p53 behavior in light of our current knowledge regarding amyloid proteins, prionoids and prions.

Role of melatonin in regulating neurogenesis: Implications for the neurodegenerative pathology and analogous therapeutics for Alzheimer’s disease

2020 ◽  
Vol 3 (2) ◽  
pp. 216-242 ◽  
Author(s):  
Mayuri Shukla ◽  
Areechun Sotthibundhu ◽  
Piyarat Govitrapong
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Adult Neurogenesis ◽  
Adult Brain ◽  
Therapeutic Approaches ◽  
Therapeutic Implications ◽  
Cell Proliferation And Differentiation ◽  
Proliferation And Differentiation ◽  
Progenitor Cell Proliferation

The revelation of adult brain exhibiting neurogenesis has established that the brain possesses great plasticity and that neurons could be spawned in the neurogenic zones where hippocampal adult neurogenesis attributes to learning and memory processes. With strong implications in brain functional homeostasis, aging and cognition, various aspects of adult neurogenesis reveal exuberant mechanistic associations thereby further aiding in facilitating the therapeutic approaches regarding the development of neurodegenerative processes in Alzheimer’s Disease (AD). Impaired neurogenesis has been significantly evident in AD with compromised hippocampal function and cognitive deficits. Melatonin the pineal indolamine augments neurogenesis and has been linked to AD development as its levels are compromised with disease progression. Here, in this review, we discuss and appraise the mechanisms via which melatonin regulates neurogenesis in pathophysiological conditions which would unravel the molecular basis in such conditions and its role in endogenous brain repair. Also, its components as key regulators of neural stem and progenitor cell proliferation and differentiation in the embryonic and adult brain would aid in accentuating the therapeutic implications of this indoleamine in line of prevention and treatment of AD.   

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