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1.
Curr Cancer Drug Targets ; 20(4): 240-252, 2020.
Article in English | MEDLINE | ID: mdl-31951183

ABSTRACT

Targeting highly proliferating cells is an important issue for many types of aggressive tumors. Proliferating Cell Nuclear Antigen (PCNA) is an essential protein that participates in a variety of processes of DNA metabolism, including DNA replication and repair, chromatin organization and transcription and sister chromatid cohesion. In addition, PCNA is involved in cell survival, and possibly in pathways of energy metabolism, such as glycolysis. Thus, the possibility of targeting this protein for chemotherapy against highly proliferating malignancies is under active investigation. Currently, approaches to treat cells with agents targeting PCNA rely on the use of small molecules or on peptides that either bind to PCNA, or act as a competitor of interacting partners. Here, we describe the status of the art in the development of agents targeting PCNA and discuss their application in different types of tumor cell lines and in animal model systems.


Subject(s)
Antineoplastic Agents/pharmacology , Aptamers, Nucleotide/pharmacology , Neoplasms/drug therapy , Neoplasms/metabolism , Peptides/pharmacology , Proliferating Cell Nuclear Antigen/metabolism , Small Molecule Libraries/pharmacology , Animals , Cell Line, Tumor , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Molecular Targeted Therapy , Neoplasms/pathology
2.
J Biomed Biotechnol ; 2011: 492075, 2011.
Article in English | MEDLINE | ID: mdl-22187527

ABSTRACT

We recently showed that Magic-F1 (Met-activating genetically improved chimeric factor 1), a human recombinant protein derived from hepatocyte growth factor/scatter factor (HGF/SF) induces muscle cell hypertrophy but not progenitor cell proliferation, both in vitro and in vivo. Here, we examined the temporal and spatial expression pattern of Magic-F1 in comparison with Pax3 (paired box gene 3) transcription factor during embryogenesis. Ranging from 9.5 to 17.5 dpc (days post coitum) mouse embryos were analyzed by in situ hybridization using whole mounts during early stages of development (9.5-10.5-11.5 dpc) and cryostat sections for later stages (11.5-13.5-15.5-17.5 dpc). We found that Magic-F1 is expressed in developing organs and tissues of mesenchymal origin, where Pax3 signal appears to be downregulated respect to the wt embryos. These data suggest that Magic-F1 could be responsible of muscular hypertrophy, cooperating with Pax3 signal pathway in skeletal muscle precursor cells.


Subject(s)
Muscle, Skeletal/pathology , Recombinant Proteins/genetics , Animals , Embryo, Mammalian , Female , Gene Expression Profiling , Hypertrophy/genetics , Hypertrophy/metabolism , Immunohistochemistry , Male , Mice , Mice, Transgenic , Muscle, Skeletal/embryology , Organ Specificity , PAX3 Transcription Factor , Paired Box Transcription Factors/analysis , Paired Box Transcription Factors/genetics , Paired Box Transcription Factors/metabolism , Polymerase Chain Reaction , Pregnancy , RNA, Messenger/analysis , Recombinant Proteins/analysis , Recombinant Proteins/metabolism
3.
PLoS One ; 3(1): e1460, 2008 Jan 23.
Article in English | MEDLINE | ID: mdl-18213369

ABSTRACT

BACKGROUND: Isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD) are heterogeneous disorders with several different etiologies and they are responsible for most cases of short stature. Mutations in different genes have been identified but still many patients did not present mutations in any of the known genes. Chromosomal rearrangements may also be involved in short stature and, among others, deletions of 18q23 defined a critical region for the disorder. No gene was yet identified. METHODOLOGY/PRINCIPAL FINDINGS: We now report a balanced translocation X;18 in a patient presenting a breakpoint in 18q23 that was surprisingly mapped about 500 Kb distal from the short stature critical region. It separated from the flanking SALL3 gene a region enriched in highly conserved non-coding elements (HCNE) that appeared to be regulatory sequences, active as enhancers or silencers during embryonic development. CONCLUSION: We propose that, during pituitary development, the 18q rearrangement may alter expression of 18q genes or of X chromosome genes that are translocated next to the HCNEs. Alteration of expression of developmentally regulated genes by translocation of HCNEs may represent a common mechanism for disorders associated to isolated chromosomal rearrangements.


Subject(s)
Body Height/genetics , Chromosomes, Human, Pair 18 , Animals , Child, Preschool , Embryonic Development/genetics , Humans , In Situ Hybridization, Fluorescence , Male , Mice
4.
Gene Expr Patterns ; 7(4): 529-34, 2007 Feb.
Article in English | MEDLINE | ID: mdl-17123869

ABSTRACT

Mammalian epithelia possess specialized cellular components that provide an impermeable barrier between two different environments. In particular, in the skin, mitotically dividing cells undergo a programmed set of morphological and biochemical changes leading to the establishment of the epidermal permeability barrier (EPB) to prevent escape of moisture and entrance of toxic molecules. Many different skin proteins are involved in the process but not all have been identified. We report here the results of the expression studies of a novel gene, highly and specifically expressed in the granular layer of the epidermis and in the epithelia of the oro-pharyngeal and gastro-intestinal tracts. Our data show that during mouse development Pof1b expression is activated in the external layers of the epidermis just prior to formation of the EPB.


Subject(s)
Epidermis/embryology , Gene Expression , Microfilament Proteins/genetics , Proteins/genetics , Animals , Blotting, Northern , Embryo, Mammalian/metabolism , Epidermis/metabolism , Epithelium/metabolism , Humans , Mice , Proteins/physiology
5.
J Biomol Tech ; 17(4): 249-51, 2006 Sep.
Article in English | MEDLINE | ID: mdl-17028165

ABSTRACT

A very simple procedure for the isolation of high-quality, high-molecular-weight genomic DNA from embryonic stem cells is described. The DNA is very stable once dried and can be stored for long periods of time without refrigeration. Living cells are lysed in a sodium dodecyl sulfate and EDTA buffer containing proteinase K and then air-dried. Samples can be processed in bulk, and an individual can easily process thousands of samples for extraction and shipment on a daily basis using only common laboratory materials such as plastic ware and a multichannel pipetteman.


Subject(s)
DNA/isolation & purification , Embryonic Stem Cells/chemistry , Embryonic Stem Cells/cytology , Genome , Specimen Handling/methods , Alleles , Animals , Cells, Cultured , Clone Cells , DNA/genetics , Genes, Reporter , Green Fluorescent Proteins/metabolism , Mice , Molecular Weight , Mutation , Polymerase Chain Reaction , Temperature , Time Factors
6.
Dev Dyn ; 235(9): 2483-92, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16791844

ABSTRACT

To explore Bapx1 homeobox gene function in embryonic control of development, we employed a gain-of-function approach to complement our previous loss-of-function mutant analysis. We show that transgenic mice overexpressing Bapx1 are affected by skeletal defects including hindlimb preaxial polydactyly and tibial hypoplasia. Bapx1 overexpression generates limb anteroposterior patterning defects including induction of Shh signaling and ectopic activation of functions downstream of Shh signaling into the anterior region of the autopod. Moreover, Bapx1 overexpression stimulates formation of limb prechondrogenic condensations. We also show that Shh is reciprocally able to activate Bapx1 expression in mouse embryos as the orthologous hedgehog (hh) does with the bagpipe/Bapx1 gene in Drosophila. Our results indicate that Bapx1 can modulate appendicular skeletal formation, that the genetic hierarchy between Shh/hh and Bapx1/bagpipe has been conserved during evolution, and that in mouse embryos these two genes can influence one another in a genetically reciprocal manner. We conclude that it is reasonable to expect overexpression of Bapx1 in certain forms of polydactyly.


Subject(s)
Extremities/embryology , Homeodomain Proteins/genetics , Polydactyly/genetics , Trans-Activators/genetics , Transcription Factors/genetics , Animals , Apoptosis , Body Patterning/genetics , Cell Proliferation , Chondrogenesis/genetics , Female , Gene Expression Regulation, Developmental , Genes, Homeobox , Hedgehog Proteins , Mice , Mice, Transgenic , Pregnancy , Signal Transduction
7.
Mech Dev ; 118(1-2): 161-3, 2002 Oct.
Article in English | MEDLINE | ID: mdl-12351180

ABSTRACT

The fork head domain-containing gene family (Fox) comprises over 20 members in mammals and is defined by a conserved 110 amino-acid motif containing a winged helix structure DNA-binding domain. The members of this gene family have been implicated as key regulators of embryogenesis, cell cycling, cell lineage restriction and cancer. The Foxn2 gene (Ches1) is expressed in postgastrulation embryos in multiple tissues that serve as important signaling centers as well as end-stage-differentiated cell types that arise from different germ layers of the developing embryo. The dynamic and specific expression of Foxn2 during embryonic development suggest multiple independent roles for Foxn2 function during gestation.


Subject(s)
Central Nervous System/embryology , DNA-Binding Proteins/biosynthesis , DNA-Binding Proteins/genetics , Embryo, Mammalian/metabolism , Gene Expression Regulation, Developmental , Amino Acid Motifs , Animals , Cell Differentiation , Cell Lineage , DNA/metabolism , DNA, Complementary/metabolism , Expressed Sequence Tags , Forkhead Transcription Factors , Gastrula/metabolism , In Situ Hybridization , Mice , Protein Binding , RNA/metabolism , Signal Transduction , Time Factors
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