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Journal of Cellular Biochemistry Nov 2018Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is...
Mouse double minute 2 (Mdm2) is a multifaceted oncoprotein that is highly regulated with distinct domains capable of cellular transformation. Loss of Mdm2 is embryonically lethal, making it difficult to study in a mouse model without additional genetic alterations. Global overexpression through increased Mdm2 gene copy number (Mdm2 ) results in the development of hematopoietic neoplasms and sarcomas in adult animals. In these mice, we found an increase in osteoblastogenesis, differentiation, and a high bone mass phenotype. Since it was difficult to discern the cell lineage that generated this phenotype, we generated osteoblast-specific Mdm2 overexpressing (Mdm2 ) mice in 2 different strains, C57BL/6 and DBA. These mice did not develop malignancies; however, these animals and the MG63 human osteosarcoma cell line with high levels of Mdm2 showed an increase in bone mineralization. Importantly, overexpression of Mdm2 corrected age-related bone loss in mice, providing a role for the proto-oncogenic activity of Mdm2 in bone health of adult animals.
Topics: Analysis of Variance; Animals; Bone Density; Bone Remodeling; Calcification, Physiologic; Cancellous Bone; Cell Line, Tumor; Female; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Osteoblasts; Osteoclasts; Osteogenesis; Osteosarcoma; Proto-Oncogene Mas; Proto-Oncogene Proteins c-mdm2; Proto-Oncogenes
PubMed: 30011084
DOI: 10.1002/jcb.27133 -
Journal of Hematology & Oncology Mar 2021The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an... (Review)
Review
The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1-2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Proto-Oncogene Proteins c-ret; Proto-Oncogenes
PubMed: 33771190
DOI: 10.1186/s13045-021-01063-9 -
Proceedings of the National Academy of... Sep 2009We describe the role of PSF protein and VL30-1 RNA, a mouse retroelement noncoding RNA, in the reversible regulation of proto-oncogene transcription, cell proliferation,...
We describe the role of PSF protein and VL30-1 RNA, a mouse retroelement noncoding RNA, in the reversible regulation of proto-oncogene transcription, cell proliferation, and tumorigenesis in mice. The experiments involved increasing expression of PSF or VL30-1 RNA in NIH/3T3 fibroblast cells and B16F10 melanoma cells by transfecting the respective coding genes under control of a strong promoter or decreasing expression by transfecting a shRNA construct that causes degradation of PSF mRNA or VL30-1 RNA. The results are as follows: (i) PSF binds to the proto-oncogene Rab23, repressing transcription, and VL30-1 RNA binds and releases PSF from Rab23, activating transcription; (ii) increasing expression of PSF or decreasing expression of VL30-1 RNA suppresses cell proliferation in culture and tumorigenesis in mice; and (iii) decreasing expression of PSF or increasing expression of VL30-1 RNA promotes cell proliferation in culture and tumorigenesis in mice. These results indicate that PSF is a major tumor-suppressor protein and VL30-1 RNA is a major tumor-promoter RNA in mice. Although VL30-1 RNA can integrate into the cell genome, tumor promotion by VL30-1 RNA involves a trans effect rather than a cis effect on gene transcription. Expression of VL30-1 RNA is 5- to 8-fold higher in mouse tumor lines than in mouse fibroblast or myoblast lines, whereas expression of PSF mRNA does not decrease in the tumor lines, suggesting that tumorigenesis is driven by an increase of VL30-1 RNA rather than a decrease of PSF. A similar regulatory mechanism functions in human cells, except that human PSF-binding RNAs replace VL30-1 RNA, which is not encoded in the human genome. We propose that PSF protein and PSF-binding RNAs have a central role in the reversible regulation of mammalian cell proliferation and tumorigenesis and that increasing PSF expression or decreasing PSF-binding RNA expression in tumor cells is a potential therapeutic strategy for cancer.
Topics: Animals; Cell Differentiation; Cell Proliferation; Cell Transformation, Neoplastic; Fibroblasts; Humans; Mice; NIH 3T3 Cells; Neoplasms, Experimental; PTB-Associated Splicing Factor; Proto-Oncogene Mas; Proto-Oncogenes; RNA; RNA, Untranslated; RNA-Binding Proteins; Retroelements; Transcription, Genetic; rab GTP-Binding Proteins
PubMed: 19805375
DOI: 10.1073/pnas.0909022106 -
The Journal of Investigative... Dec 1999Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2... (Review)
Review
Hair follicle (HF) morphogenesis and cycling are characterized by a tightly controlled balance of proliferation, differentiation and apoptosis. The members of the bcl-2 family of proto-oncogenes are important key players in the apoptosis control machinery of most cell types. Bcl-2, an apoptosis inhibitor, and Bax, an apoptosis promoter, show tightly regulated, hair cycle-dependent expression patterns: during catagen, the distal ORS of the HF remains strongly positive for Bcl-2 and Bax; in contrast, the proximal epithelial part of the HF loses most Bcl-2 expression while it remains strongly positive for Bax. In Bcl-2 null mice, skin becomes markedly hypopigmented during the first postnatal anagen probably due to increased melanocyte apoptosis. Reportedly, these mice also show a retardation of the first anagen development after birth. Transgenic mice overexpressing Bcl-2 under the control of the keratin-1 promoter display multifocal epidermal hyperplasia and aberrant expression of keratin-6, while alterations of HF cycling have not been investigated. Surprisingly, Bcl-2 overexpression under the control of the keratin-14 promoter leads to accelerated catagen progression and increased chemotherapy-induced apoptosis, HF dystrophy and alopecia. Transgenic mice overexpressing Bcl-X(L), another anti-apoptotic bcl-2 family member, under the control of the K14 promoter, reportedly also display accelerated catagen development. These and other Bcl-2 transgenic and null mice are now available to further dissect the as yet unclear, and likely complex, role of Bcl-2 in HF growth and pigmentation.
Topics: Animals; Apoptosis; Gene Expression Regulation; Genes, bcl-2; Hair Follicle; Mice; Mice, Knockout; Mice, Transgenic; Proto-Oncogene Proteins c-bcl-2
PubMed: 10674380
DOI: 10.1038/sj.jidsp.5640228 -
Molecular and Cellular Biology Jan 1989Molecular analysis of the human trk oncogene, a transforming gene isolated from a colon carcinoma biopsy, revealed the existence of a novel member of the tyrosine kinase...
Molecular analysis of the human trk oncogene, a transforming gene isolated from a colon carcinoma biopsy, revealed the existence of a novel member of the tyrosine kinase gene family. This locus, which we now designate the trk proto-oncogene, codes for a protein of 790 amino acid residues that has several features characteristic of cell surface receptors. They include (i) a 32-amino-acid-long putative signal peptide, (ii) an amino-terminal moiety (residues 33 to 407) rich in consensus sites for N-glycosylation, (iii) a transmembrane domain, (iv) a kinase catalytic region highly related to that of other tyrosine kinases, and (v) a very short (15 residue) carboxy-terminal tail. Residues 1 to 392 were absent in the trk oncogene, as they were replaced by tropomyosin sequences. However, no other differences were found between the transforming and nontransforming trk alleles (residues 392 to 790), suggesting that no additional mutations are required to activate the transforming potential of this gene. The human trk proto-oncogene codes for a 140,000-dalton glycoprotein, designated gp140proto-trk. However, its primary translational product is a 110,000-dalton glycoprotein which becomes immediately glycosylated, presumably during its translocation into the endoplasmic reticulum. This molecule, designated gp110proto-trk, is further glycosylated to yield the mature form, gp140proto-trk. Both gp110proto-trk and gp140proto-trk proteins possess in vitro kinase activity specific for tyrosine residues. Finally, iodination of intact NIH 3T3 cells expressing trk proto-oncogene products indicated that only the mature form, gp140proto-trk, cross the plasma membrane, becoming exposed to the outside of the cell. These results indicate that the product of the human trk locus is a novel tyrosine kinase cell surface receptor for an as yet unknown ligand.
Topics: Amino Acid Sequence; Base Sequence; DNA; DNA, Recombinant; Gene Expression Regulation; Genetic Vectors; Humans; Molecular Sequence Data; Plasmids; Precipitin Tests; Protein-Tyrosine Kinases; Proto-Oncogene Mas; Proto-Oncogenes
PubMed: 2927393
DOI: 10.1128/mcb.9.1.24-33.1989 -
Journal of Medical Genetics Jan 1994Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have... (Review)
Review
Details are given of 214 loci known to be associated with human hereditary disease, which have been mapped on both human and mouse chromosomes. Forty two of these have pathological variants in both species; in general the mouse variants are similar in their effects to the corresponding human ones, but exceptions include the Dmd/DMD and Hprt/HPRT mutations which cause little, if any, harm in mice. Possible reasons for phenotypic differences are discussed. In most pathological variants the gene product seems to be absent or greatly reduced in both species. The extensive data on conserved segments between human and mouse chromosomes are used to predict locations in the mouse of over 50 loci of medical interest which are mapped so far only on human chromosomes. In about 80% of these a fairly confident prediction can be made. Some likely homologies between mapped mouse loci and unmapped human ones are also given. Sixty six human and mouse proto-oncogene and growth factor gene homologies are also listed; those of confirmed location are all in known conserved segments. A survey of 18 mapped human disease loci and chromosome regions in which the manifestation or severity of pathological effects is thought to be the result of genomic imprinting shows that most of the homologous regions in the mouse are also associated with imprinting, especially those with homologues on human chromosomes 11p and 15q. Useful methods of accelerating the production of mouse models of human hereditary disease include (1) use of a supermutagen, such as ethylnitrosourea (ENU), (2) targeted mutagenesis involving ES cells, and (3) use of gene transfer techniques, with production of 'knockout mutations'.
Topics: Animals; Chromosome Mapping; Genetic Diseases, Inborn; Genetic Variation; Humans; Mice; Proto-Oncogene Mas; Proto-Oncogenes; Species Specificity
PubMed: 8151633
DOI: 10.1136/jmg.31.1.1 -
The International Journal of... Sep 1991Growth factors and proto-oncogenes play an important role in the regulation of embryonic growth and differentiation as well as in tumorigenesis. Insulin and insulin-like... (Review)
Review
Growth factors and proto-oncogenes play an important role in the regulation of embryonic growth and differentiation as well as in tumorigenesis. Insulin and insulin-like growth factor I (IGF I) are secreted by embryonic tissues during the prepancreatic stage of mouse development. Measureable amounts of these factors were found in 8- to 12-day-old embryos. Embryonic cells derived from 8- to 10-day-old embryos secrete insulin and IGF I in serum-free medium. Relatively high levels of c-myc, c-fos and c-H-ras oncoproteins were also detected in 8- to 12-day-old embryos. Insulin and IGF I, when added to the culture of embryonic cells, stimulate their proliferation. Similar results were obtained in some animal or human tumors. Murine myeloid leukemias and melanoma B 16 secrete a substance immunologically cross reactive with insulin (SICRI) both in vivo and in serum-free media. In culture, the DNA synthesis rate per leukemic or melanoma cell is proportional to cell density and is reduced by antiinsulin serum in case of leukemic cells. Human hemangiosarcoma secrete IGF I, which also plays a role as an autocrine factor. Purified IGF I efficiently induce c-myc and c-fos mRNA, which is among the earliest events following growth factor stimulation, leading to mitosis. These results lead us to the conclusion that IGF I and insulin together with oncoproteins stimulate the growth of embryonic and tumor cells, which is indirect evidence for a paracrine (or autocrine) type of action.
Topics: Animals; Cell Division; Gene Expression Regulation; Growth Substances; Insulin; Mice; Morphogenesis; Proto-Oncogene Proteins; Proto-Oncogenes
PubMed: 1814404
DOI: No ID Found -
Environmental Health Perspectives Jun 1991The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of... (Review)
Review
The use of the mouse skin multistage model of carcinogenesis has aided our understanding of critical target genes in chemical carcinogenesis. The mutagenic activation of the Harvey-ras proto-oncogene has been found to be an early event associated with the initiation of mouse skin tumors by the polycyclic aromatic hydrocarbon 7,12 dimethylbenz[alpha]anthracene and the pure initiator ethyl carbamate (urethane). In contrast to chemical initiation of mouse skin tumors, ionizing radiation-initiated malignant skin tumors have been shown to possess distinct non-ras transforming gene(s). Differential screening of cDNA libraries made from chemically initiated malignant skin tumors has been used to identify a number of cellular gene transcripts that are overexpressed during mouse skin tumor progression. These differentially expressed genes include beta-actin, ubiquitin, a hyperproliferative keratin (K6), a gene whose product is a member of a fatty acid or lipid-binding protein family, and a gene called transin or stromelysin. The overexpression of the stromelysin gene, which encodes a metalloproteinase that degrades proteins in the basement membrane, is hypothesized to play a functional role in malignant tumor cell invasion and metastasis. We believe that the cloning, identification, and characterization of gene sequences that are differentially expressed during tumor progression could lead to the discovery of gene products that either play functional roles in skin tumor progression or in the maintenance of various progressive tumor phenotypes.
Topics: 3T3 Cells; Animals; Carcinogens; Carcinoma, Squamous Cell; Cell Line, Transformed; Cell Transformation, Neoplastic; Cocarcinogenesis; DNA Damage; DNA, Neoplasm; Gene Expression Regulation, Neoplastic; Genes, Dominant; Genes, ras; Matrix Metalloproteinase 3; Metalloendopeptidases; Mice; Neoplasms, Multiple Primary; Neoplasms, Radiation-Induced; Papilloma; Proto-Oncogenes; Skin Neoplasms
PubMed: 1773801
DOI: 10.1289/ehp.919351 -
The British Journal of Ophthalmology Feb 1999Ultraviolet (UV) irradiation of mammalian cells in culture evokes the transcriptional activation of different proto-oncogenes, among them members of the fos/jun family...
BACKGROUND/AIMS
Ultraviolet (UV) irradiation of mammalian cells in culture evokes the transcriptional activation of different proto-oncogenes, among them members of the fos/jun family which are known to play an important role in cell proliferation and differentiation. To investigate in vivo UV induced proto-oncogene expression of irradiated ocular cells, the expression of JunB, JunD, and Egr-1 was analysed in the cornea, lens, and retina. Furthermore, UV radiation is known to induce pleiotrophic events in irradiated cells which include growth arrest, inflammation, and even cell death. In order to determine the type of cell death--for example, apoptosis versus necrosis, sections of UV irradiated rat eyes were further examined for distinct ultrastructural morphology of cell death and DNA fragmentation.
METHODS
Eyes of anaesthetised rats were exposed to 1.5 J/cm2 of ultraviolet radiation (280-380 nm). Animals were perfused 6 and 16 hours after irradiation and tissue sections of enucleated bulbi were processed for light and electron microscopy.
RESULTS
Under control conditions, Jun B was constitutively expressed in numerous superficial cells but also in scattered basal cells of the corneal epithelium. After UV exposure JunB expression was massively upregulated in many cells of the basal cell layers of the corneal epithelium, although during the entire experiment, both the corneal stroma and endothelium were JunB negative. In contrast, Egr-1 was expressed exclusively in lens epithelium showing only a faint expression pattern under control conditions. However, Egr-1 expression increased after UV exposure, so that many Egr-1 positive cells of the lens epithelium could be found several hours after UV illumination. JunD was expressed in single cells of both the ganglion cell layer and the inner nuclear layer of the retina, a pattern of expression which did not change after UV exposure. Regarding the type of cell death, features of apoptosis were only occasionally present in scattered superficial cells of the corneal epithelium of control eyes. After UV exposure, however, morphological signs of apoptosis and TUNEL positive cells were visible both in the stroma and epithelium of the rat cornea. In contrast, UV irradiated lens epithelial cells exhibited features typical of necrosis. The corneal endothelium and the retina did not show any indications of morphological changes indicative of cell death after UV irradiation.
CONCLUSION
Each proto-oncogene encoded protein was found to be expressed in a tissue specific manner and UV irradiation differentially modulates the expression pattern of these transcriptional regulatory proteins. This temporospatial expression pattern of these proteins is accompanied by two morphologically distinct types of cell death in the cornea and lens after UV irradiation.
Topics: Animals; Apoptosis; Epithelium, Corneal; Eye; Gene Expression Regulation; Immunohistochemistry; Lens, Crystalline; Male; Proto-Oncogenes; Rats; Rats, Sprague-Dawley; Ultraviolet Rays
PubMed: 10396203
DOI: 10.1136/bjo.83.2.225 -
The Biochemical Journal Mar 1996The myc family of proto-oncogenes is believed to be involved in the establishment of many types of human malignancy. The members of this family have been shown to... (Review)
Review
The myc family of proto-oncogenes is believed to be involved in the establishment of many types of human malignancy. The members of this family have been shown to function as transcription factors, and through a designated target sequence bring about continued cell-cycle progression, cellular immortalization and blockages to differentiation in many lineages. However, while much of the recent work focusing on the c-myc oncogene has provided some very important advances, it has also brought to light a large amount of conflicting data as to the mechanism of action of the gene product. In this regard, it has now been shown that c-myc is effective in transcriptional repression as well as transcriptional activation and, perhaps more paradoxically, that it has a role in programmed cell death (apoptosis) as well as in processes of cell-cycle progression. In addition, particular interest has surrounded the distinct roles of the two alternative translation products of the c-myc gene, c-Myc 1 and c-Myc 2. The intriguing observation that the ratio of c-Myc 1 to c-Myc 2 increases markedly upon cellular quiescence led to the discovery that the enforced expression of the two proteins individually showed that c-Myc 2 stimulates cell growth, whereas c-Myc 1 appears to be growth suppressing. Clearly, the disparities in the activities of c-Myc, together with the consistent occurrence of mutations of c-myc in human malignancies, means that, although reaching an understanding of the functions of the myc gene family might not be simple, it remains well worthy of pursuit.
Topics: Animals; Base Sequence; Cell Transformation, Neoplastic; Genes, myc; Humans; Multigene Family; Neoplasms; Proto-Oncogene Proteins c-myc; Substrate Specificity; Transcription Factors; Transcription, Genetic
PubMed: 8615760
DOI: 10.1042/bj3140713