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World Journal of Gastroenterology Apr 2008Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin... (Review)
Review
Several lines of evidence point towards a biological role of mucin and particularly MUC1 in colorectal cancer. A positive correlation was described between mucin secretion, proliferation, invasiveness, metastasis and bad prognosis. But, the role of MUC1 in cancer progression is still controversial and somewhat confusing. While Mukherjee and colleagues developed MUC1-specific immune therapy in a CRC model, Lillehoj and co-investigators showed recently that MUC1 inhibits cell proliferation by a beta-catenin-dependent mechanism. In carcinoma cells the polarization of MUC1 is lost and the protein is over expressed at high levels over the entire cell surface. A competitive interaction between MUC1 and E-cadherin, through beta-catenin binding, disrupts E-cadherin-mediated cell-cell interactions at sites of MUC1 expression. In addition, the complex of MUC1-beta-catenin enters the nucleus and activates T-cell factor/leukocyte enhancing factor 1 transcription factors and activates gene expression. This mechanism may be similar to that just described for DCC and UNC5H, which induced apoptosis when not engaged with their ligand netrin, but mediate signals for proliferation, differentiation or migration when ligand bound.
Topics: Cadherins; Cell Proliferation; Colorectal Neoplasms; Cytoplasm; Gastroenterology; Gastrointestinal Neoplasms; Gene Expression Regulation, Neoplastic; Humans; Ligands; Medical Oncology; Models, Biological; Mucin-1; Neoplasm Metastasis; Phosphorylation; beta Catenin
PubMed: 18407586
DOI: 10.3748/wjg.14.2139 -
Trends in Genetics : TIG Jan 2018Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control... (Review)
Review
Recent work demonstrating the role of chromosome organization in transcriptional regulation has sparked substantial interest in the molecular mechanisms that control chromosome structure. Condensin, an evolutionarily conserved multisubunit protein complex, is essential for chromosome condensation during cell division and functions in regulating gene expression during interphase. In Caenorhabditis elegans, a specialized condensin forms the core of the dosage compensation complex (DCC), which specifically binds to and represses transcription from the hermaphrodite X chromosomes. DCC serves as a clear paradigm for addressing how condensins target large chromosomal domains and how they function to regulate chromosome structure and transcription. Here, we discuss recent research on C. elegans DCC in the context of canonical condensin mechanisms as have been studied in various organisms.
Topics: Adenosine Triphosphatases; Animals; Caenorhabditis elegans; DNA-Binding Proteins; Dosage Compensation, Genetic; Female; Gene Expression Regulation; Multiprotein Complexes; X Chromosome
PubMed: 29037439
DOI: 10.1016/j.tig.2017.09.010 -
PloS One 2021The presence of autophagy has been indicated in cholangiocarcinoma (CC), which disease has poor prognosis and limited treatment options. Recently, CC has been classified... (Comparative Study)
Comparative Study
The presence of autophagy has been indicated in cholangiocarcinoma (CC), which disease has poor prognosis and limited treatment options. Recently, CC has been classified by anatomical localization as intrahepatic (iCC), perihilar (pCC) and distal (dCC), showing different clinical and molecular characteristics. Thus, our aim was to compare autophagy activity in CC samples resected from different anatomical locations. Further, we investigated whether autophagy could be modulated in cell lines originated from iCC and extrahepatic CC (eCC) following the treatments with autophagy inhibitory and inducing agents. Tissue microarrays were prepared from 70 CC (28 iCC, 19 pCC and 23 dCC), 31 adjacent non-tumorous and 9 hepatocellular carcinoma (HCC) samples. Autophagy markers LC3, p62 and Beclin1 as well as proliferation marker Ki-67 were monitored by immunohistochemistry and were associated with patients' survival. Modulation of autophagy was investigated in cell lines originated from iCC (HuH-28), eCC (TFK-1) and HCC (HepG2) by treating the cells with chloroquine (CQ) for inhibition and with Rapamycin, 5-Fluorouracil (5-FU) and Sorafenib for induction of autophagy. Our results indicated an inhibited autophagy in iCC and pCC tumor tissues, whereas active autophagy seemed to occur in dCC, especially in samples displaying low Ki-67 index. Additionally, low level of Beclin1 and high level of Ki-67 were associated with poor overall survival in dCC, suggesting the prognostic role of these proteins in dCC. Beside a baseline autophagy detected in each cell line, Rapamycin and 5-FU induced autophagy in iCC and HepG2 cell lines, Sorafenib in iCC cells. A chemotherapy agent in combination with CQ decreased IC50 effectively in the cell lines where basal and/or induced autophagy were present. In conclusion, we revealed differences in the autophagy activities of CC tissues and cell lines originated from different anatomical locations, which might influence patients' treatment. Our results also suggest a prognostic role of Beclin1 and Ki-67 in dCC.
Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Autophagy; Beclin-1; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cell Line, Tumor; Cholangiocarcinoma; Female; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Ki-67 Antigen; Klatskin Tumor; Male; Middle Aged; Neoplasm Grading; Prognosis; Survival Analysis; Tissue Array Analysis
PubMed: 34129628
DOI: 10.1371/journal.pone.0253065 -
Database : the Journal of Biological... 2015The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a catalog of genomic annotations. To date, the project has generated over... (Review)
Review
The Encyclopedia of DNA elements (ENCODE) project is an ongoing collaborative effort to create a catalog of genomic annotations. To date, the project has generated over 4000 experiments across more than 350 cell lines and tissues using a wide array of experimental techniques to study the chromatin structure, regulatory network and transcriptional landscape of the Homo sapiens and Mus musculus genomes. All ENCODE experimental data, metadata and associated computational analyses are submitted to the ENCODE Data Coordination Center (DCC) for validation, tracking, storage and distribution to community resources and the scientific community. As the volume of data increases, the organization of experimental details becomes increasingly complicated and demands careful curation to identify related experiments. Here, we describe the ENCODE DCC's use of ontologies to standardize experimental metadata. We discuss how ontologies, when used to annotate metadata, provide improved searching capabilities and facilitate the ability to find connections within a set of experiments. Additionally, we provide examples of how ontologies are used to annotate ENCODE metadata and how the annotations can be identified via ontology-driven searches at the ENCODE portal. As genomic datasets grow larger and more interconnected, standardization of metadata becomes increasingly vital to allow for exploration and comparison of data between different scientific projects.
Topics: Animals; Data Curation; Databases, Genetic; Gene Ontology; Gene Regulatory Networks; Humans; Mice; Molecular Sequence Annotation; Transcription, Genetic
PubMed: 25776021
DOI: 10.1093/database/bav010 -
Science Advances May 2023Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed...
Mirror movements (MM) disorder is characterized by involuntary movements on one side of the body that mirror intentional movements on the opposite side. We performed genetic characterization of a family with autosomal dominant MM and identified , a RhoGEF, as a candidate MM gene. We found that Arhgef7 and its partner Git1 bind directly to Dcc. Dcc is the receptor for Netrin-1, an axon guidance cue that attracts commissural axons to the midline, promoting the midline crossing of axon tracts. We show that Arhgef7 and Git1 are required for Netrin-1-mediated axon guidance and act as a multifunctional effector complex. Arhgef7/Git1 activates Rac1 and Cdc42 and inhibits Arf1 downstream of Netrin-1. Furthermore, Arhgef7/Git1, via Arf1, mediates the Netrin-1-induced increase in cell surface Dcc. Mice heterozygous for have defects in commissural axon trajectories and increased symmetrical paw placements during skilled walking, a MM-like phenotype. Thus, we have delineated how mutation causes MM.
Topics: Mice; Animals; DCC Receptor; Tumor Suppressor Proteins; Nerve Growth Factors; Netrin-1; Receptors, Cell Surface; Axons
PubMed: 37172092
DOI: 10.1126/sciadv.add5501 -
Human Mutation Jan 2018The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline... (Review)
Review
The deleted in colorectal cancer (DCC) gene encodes the netrin-1 (NTN1) receptor DCC, a transmembrane protein required for the guidance of commissural axons. Germline DCC mutations disrupt the development of predominantly commissural tracts in the central nervous system (CNS) and cause a spectrum of neurological disorders. Monoallelic, missense, and predicted loss-of-function DCC mutations cause congenital mirror movements, isolated agenesis of the corpus callosum (ACC), or both. Biallelic, predicted loss-of-function DCC mutations cause developmental split brain syndrome (DSBS). Although the underlying molecular mechanisms leading to disease remain poorly understood, they are thought to stem from reduced or perturbed NTN1 signaling. Here, we review the 26 reported DCC mutations associated with abnormal CNS development in humans, including 14 missense and 12 predicted loss-of-function mutations, and discuss their associated clinical characteristics and diagnostic features. We provide an update on the observed genotype-phenotype relationships of congenital mirror movements, isolated ACC and DSBS, and correlate this to our current understanding of the biological function of DCC in the development of the CNS. All mutations and their associated phenotypes were deposited into a locus-specific LOVD (https://databases.lovd.nl/shared/genes/DCC).
Topics: Abnormalities, Multiple; Agenesis of Corpus Callosum; Amino Acid Sequence; Binding Sites; Conserved Sequence; Databases, Genetic; Genes, DCC; Genetic Association Studies; Humans; Magnetic Resonance Imaging; Models, Molecular; Mutation; Netrin-1; Phenotype; Protein Binding; Protein Conformation; Protein Domains; Syndrome
PubMed: 29068161
DOI: 10.1002/humu.23361 -
Scientific Reports Feb 2017During development, midline crossing by axons brings into play highly conserved families of receptors and ligands. The interaction between the secreted ligand Netrin-1...
During development, midline crossing by axons brings into play highly conserved families of receptors and ligands. The interaction between the secreted ligand Netrin-1 and its receptor Deleted in Colorectal Carcinoma (DCC) is thought to control midline attraction of crossing axons. Here, we studied the evolution of this ligand/receptor couple in birds taking advantage of a wealth of newly sequenced genomes. From phylogeny and synteny analyses we can infer that the DCC gene has been conserved in most extant bird species, while two independent events have led to its loss in two avian groups, passeriformes and galliformes. These convergent accidental gene loss events are likely related to chromosome Z rearrangement. We show, using whole-mount immunostaining and 3Disco clearing, that in the nervous system of all birds that have a DCC gene, DCC protein expression pattern is similar to other vertebrates. Surprisingly, we show that the early developmental pattern of commissural tracts is comparable in all birds, whether or not they have a DCC receptor. Interestingly, only 4 of the 5 genes encoding secreted netrins, the DCC ligands in vertebrates, were found in birds, but Netrin-5 was absent. Together, these results support a remarkable plasticity of commissural axon guidance mechanisms in birds.
Topics: Animals; Avian Proteins; Axon Guidance; Axons; Biological Evolution; Birds; Brain; Conserved Sequence; DCC Receptor; Netrin-1; Neuronal Plasticity; Neurons; Phylogeny; Sequence Deletion; Vertebrates
PubMed: 28240285
DOI: 10.1038/srep37569 -
Cellular and Molecular Life Sciences :... Nov 2005Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H.... (Review)
Review
Netrin-1 has been shown to play a crucial role in neuronal navigation during nervous system development mainly through its interaction with its receptors DCC and UNC5H. However, initially the DCC (deleted in colorectal cancer) gene was proposed as a putative tumor suppressor gene. It was then difficult to reconcile the two activities of DCC until the observation that DCC belongs to an emerging family of receptors named dependence receptors. Such receptors share the property of inducing apoptosis in the absence of ligand, hence creating a cellular state of dependence on the ligand. Thus, netrin-1 may not only be a chemotropic factor for neurons but also a survival factor. We will review here the identification of netrin-1 and its receptors, the signaling pathways initiated in the presence or absence of netrin-1. We will suggest some possible roles of netrin-1 in nervous system development, neovascularisation, adhesion and tumorigenesis.
Topics: Animals; Chemotactic Factors; Humans; Neoplasms; Nerve Growth Factors; Netrin-1; Neurons; Tumor Suppressor Proteins
PubMed: 16158190
DOI: 10.1007/s00018-005-5191-3 -
Cortex; a Journal Devoted To the Study... Apr 2023Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological...
Corpus callosum dysgenesis is a congenital abnormality whereby the corpus callosum fails to develop normally, and has been associated with a range of neuropsychological outcomes. One specific finding in some individuals with corpus callosum dysgenesis is "congenital mirror movement disorder", which is the presence of involuntary movements on one side of the body that mimic voluntary movements of the other side. Mirror movements have also been associated with mutations in the deleted in colorectal carcinoma (DCC) gene. The current study aims to comprehensively document the neuropsychological outcomes and neuroanatomical mapping of a family (a mother, daughter and son) with known DCC mutations. All three family members experience mirror movements, and the son additionally has partial agenesis of the corpus callosum (pACC). All family members underwent extensive neuropsychological testing, spanning general intellectual functioning, memory, language, literacy, numeracy, psychomotor speed, visuospatial perception, praxis and motor functioning, executive functioning, attention, verbal/nonverbal fluency, and social cognition. The mother and daughter had impaired memory for faces, and reduced spontaneous speech, and the daughter demonstrated scattered impairments in attention and executive functioning, but their neuropsychological abilities were largely within normal limits. By contrast, the son showed areas of significant impairment across multiple domains including reduced psychomotor speed, fine motor dexterity and general intellectual functioning, and he was profoundly impaired across areas of executive functioning and attention. Reductions in his verbal/non-verbal fluency, with relatively intact core language, resembled dynamic frontal aphasia. His relative strengths included aspects of memory and he demonstrated largely sound theory of mind. Neuroimaging revealed an asymmetric sigmoid bundle in the son, connecting, via the callosal remnant, the left frontal cortex with contralateral parieto-occipital cortex. Overall, this study documents a range of neuropsychological and neuroanatomical outcomes within one family with DCC mutations and mirror movements, including one with more severe consequences and pACC.
Topics: Female; Humans; Male; Agenesis of Corpus Callosum; Corpus Callosum; DCC Receptor; Movement Disorders; Mutation; Neuroimaging
PubMed: 36889039
DOI: 10.1016/j.cortex.2023.01.008 -
British Journal of Cancer Feb 2000To clarify the possible role of DCC gene alteration in ovarian neoplasias, we immunohistochemically investigated 124 carcinomas, as well as 55 cystadenomas and 41 low...
To clarify the possible role of DCC gene alteration in ovarian neoplasias, we immunohistochemically investigated 124 carcinomas, as well as 55 cystadenomas and 41 low malignant potential (LMP) tumours and compared the results with those for p53 protein expression, clinicopathological factors and survival. A combination of the reverse transcription polymerase chain reaction (RT-PCR) and Southern blot hybridization (SBH) for DCC mRNA levels was also carried out on 26 malignant, five LMP, eight benign and seven normal ovarian samples. Significantly decreased levels of overall DCC values in carcinomas compared with benign and LMP lesions were revealed by both immunohistochemical and RT-PCR/SBH assays. Similar findings were also noted when subdivision was into serous and mucinous categories. In carcinomas, reduction or loss of DCC expression was significantly related to the serous phenotype (serous vs non-serous, P < 0.0001), a high histological grade (grade 1 vs 2 or 3, P < 0.02) and a more advanced stage (FIGO stage I vs II/III/IV, P = 0.0083), while no association was noted with survival. Although p53 immunopositivity demonstrated significant stepwise increase from benign through to malignant lesions, there was no clear association with DCC score values. The results indicated that impaired DCC expression may play an important role in ovarian tumorigenesis. In ovarian carcinomas, the altered expression is closely linked with tumour differentiation and progression.
Topics: Base Sequence; Blotting, Southern; Cell Adhesion Molecules; Cell Differentiation; DCC Receptor; DNA Primers; Disease Progression; Female; Gene Expression Regulation, Neoplastic; Genes, DCC; Humans; Immunohistochemistry; Ovarian Neoplasms; Prognosis; RNA, Messenger; Receptors, Cell Surface; Reverse Transcriptase Polymerase Chain Reaction; Survival Analysis; Tumor Suppressor Protein p53; Tumor Suppressor Proteins
PubMed: 10682668
DOI: 10.1054/bjoc.1999.0966