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Blood Jul 1993Programmed cell death (apoptosis) is a normal process by which cells are eliminated during normal embryonic development and in adult life. Disruption of this normal... (Review)
Review
Programmed cell death (apoptosis) is a normal process by which cells are eliminated during normal embryonic development and in adult life. Disruption of this normal process resulting in illegitimate cell survival can cause developmental abnormalities and facilitate cancer development. Normal cells require certain viability factors and undergo programmed cell death when these factors are withdrawn. The viability factors are required throughout the differentiation process from immature to mature cells. Although many viability factors are also growth factors, viability and growth are separately regulated. Viability factors can have clinical value in decreasing the loss of normal cells including the loss that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that occurs after irradiation, exposure to other cytotoxic agents or virus infection including AIDS. There is no evidence that cancer cells are immortal. Programmed cell death can be induced in leukemic cells by removal of viability factors, by cytotoxic therapeutic agents, or by the tumor-suppressor gene wild-type p53. All these forms of induction of programmed cell death in leukemic cells can be suppressed by the same viability factors that suppress programmed cell death in normal cells. A tumor-promoting phorbol ester can also suppress this death program. The induction of programmed cell death can be enhanced by deregulated expression of the gene c-myc and suppressed by the gene bcl-2. Mutant p53 and bcl-2 suppress the enhancing effect on cell death of deregulated c-myc, and thus allow induction of cell proliferation and inhibition of differentiation which are other functions of deregulated c-myc. The suppression of cell death by mutant p53 and bcl-2 increases the probability of developing cancer. The suppression of programmed cell death in cancer cells by viability factors suggests that decreasing the level of these factors may increase the effectiveness of cytotoxic cancer therapy. Treatments that downregulate the expression or activity of mutant p53 and bcl-2 in cancer cells should also be useful for therapy.
Topics: Apoptosis; Cell Survival; Gene Expression; Genes, myc; Genes, p53; Granulocyte-Macrophage Colony-Stimulating Factor; Hematopoietic Stem Cells; Humans; Leukemia; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogenes; RNA, Messenger; Tumor Cells, Cultured
PubMed: 8324219
DOI: No ID Found -
Cancer Research Jan 2013PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility,...
PTEN is a well-defined tumor suppressor gene that antagonizes the PI3K/Akt pathway to regulate a multitude of cellular processes, such as survival, growth, motility, invasiveness, and angiogenesis. While the functions of PTEN have been studied extensively, the regulation of its activity during normal and disease conditions still remains incompletely understood. In this study, we identified the protein phosphatase-1 nuclear targeting subunit PNUTS (PPP1R10) as a PTEN-associated protein. PNUTS directly interacted with the lipid-binding domain (C2 domain) of PTEN and sequestered it in the nucleus. Depletion of PNUTS leads to increased apoptosis and reduced cellular proliferation in a PTEN-dependent manner. PNUTS expression was elevated in certain cancers compared with matched normal tissues. Collectively, our studies reveal PNUTS as a novel PTEN regulator and a likely oncogene.
Topics: Cell Line, Tumor; Cell Nucleus; DNA-Binding Proteins; Fluorescent Antibody Technique; Humans; Immunoblotting; Immunohistochemistry; Immunoprecipitation; Neoplasms; Nuclear Proteins; PTEN Phosphohydrolase; Protein Transport; Proto-Oncogene Mas; Proto-Oncogenes; RNA Interference; RNA, Small Interfering; RNA-Binding Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transfection
PubMed: 23117887
DOI: 10.1158/0008-5472.CAN-12-1394 -
International Journal of Cell Cloning Jul 1987Oncogenes are a class of genes hypothesized to be causally related to neoplasia. To date, specific oncogenes have been recognized chiefly by their ability to transform... (Review)
Review
Oncogenes are a class of genes hypothesized to be causally related to neoplasia. To date, specific oncogenes have been recognized chiefly by their ability to transform test cells to a neoplastic phenotype. This has been accomplished largely through mutational analysis of the genotype of retroviruses or through the analysis of tumor cell DNA by in vitro transfection of rodent fibroblasts. Oncogenes are believed to arise by some genetic alteration from normal cellular genes called proto-oncogenes. Although the normal function of most proto-oncogenes is unknown, it has been proposed that they may function as tissue-specific and temporally specific regulators of differentiation. The role of oncogenes in lymphoid malignancies has been extensively analyzed. Less is known about their role in myeloid leukemias and especially in normal myelopoiesis. Space limitations permit discussion of only salient features of a limited number of oncogenes; we have arbitrarily selected myc, myb, fos, fms, fes, sis, and abl.
Topics: Animals; Cell Line; Cell Transformation, Neoplastic; Gene Expression Regulation; Hematopoiesis; Humans; Leukemia, Myeloid; Oncogenes; Proto-Oncogenes
PubMed: 3305725
DOI: 10.1002/stem.5530050402 -
The American Journal of Pathology Oct 1990To study the mechanism(s) of vascular smooth muscle cell proliferation in vivo, mRNA levels of c-fos, c-jun, and c-myc were determined by Northern blot analysis...
To study the mechanism(s) of vascular smooth muscle cell proliferation in vivo, mRNA levels of c-fos, c-jun, and c-myc were determined by Northern blot analysis following vascular balloon de-endothelialization (BDE). Medial smooth muscle cells (SMC) were separated and studied by enzymatic digestion of the vessel wall. mRNA levels of c-fos and c-jun from aortic smooth muscle cells (SMC) were simultaneously induced within 30 minutes of BDE and declined to baseline by 1.5 hours, c-myc mRNA did not begin to increase until 1 hour after vascular injury. Levels of c-myc peaked at 2 hours and were sustained for an additional 4 hours before gradually declining. Smooth muscle cells derived from enzyme-treated control aortae that did not undergo BDE expressed c-fos and c-jun, but showed no evidence of c-myc message. In contrast, nonenzymatically treated, non-BDE whole aortae (containing both media and adventitia) demonstrated a prominent c-myc signal, but failed to express c-fos and c-jun. Corresponding examination of adventitia derived from enzyme-treated aortae showed this tissue to be a source of all three proto-oncogenes. The results of this study demonstrate the earliest in vivo molecular markers of vascular injury reported to date and implicate SMC proto-oncogene expression in the initiation of SMC proliferation. Furthermore these findings suggest two avenues for proto-oncogene induction, that are due to (1) vessel wall manipulation and (2) humoral stimulation.
Topics: Animals; Aorta; Cell Division; DNA Probes; Endothelium, Vascular; Gene Expression; Male; Models, Biological; Muscle, Smooth, Vascular; Proto-Oncogenes; RNA, Messenger; Rats; Rats, Inbred Strains
PubMed: 2221010
DOI: No ID Found -
Biochemical and Biophysical Research... Sep 2019The cytoplasmic distribution of the HuR/ELAVL1 (embryonic lethal abnormal vision 1) protein is recognized as an important prognostic factor of malignant tumors. However,...
The cytoplasmic distribution of the HuR/ELAVL1 (embryonic lethal abnormal vision 1) protein is recognized as an important prognostic factor of malignant tumors. However, the previous study suggests that exogenous over-expression of HuR is not sufficient for nuclear export. Conversely, the predominantly cytosolic distribution of neuron-specific human ELAV members, including HuB/ELAVL2, HuC/ELAVL3, and HuD/ELAVL4, has been reported. In the present study, we demonstrated the expression of HuB in several types of cancer cells, but expression of HuC and HuD was not observed. In addition, our results indicated that HuR and HuB formed a complex in the cytosolic fraction of cancer cells via the RRM3 region. Ectopic expression of HuB was capable of initiating the cytosolic translocation of HuR from the nucleus to the cytosol. Furthermore, HuB-transduced cancer cells displayed significant nuclear export of HuR, with quantitative PCR experiments revealing the simultaneous upregulation of HIF-1α, c-Fos, c-MYC, and Ets2 basal mRNA expression. Phorbol 12-myristate 13-acetate (PMA)-stimulated HuB-transduced cells demonstrated significantly enhanced activation of endogenous c-Fos and CREB dependent cascades. Finally, co-transfection of HuB with the E1 region of type 5 human adenovirus significantly enhanced E1 transformation activities but that of HuR with the E1 region did not. Collectively, our findings suggest that the neural Hu family protein HuB plays a major role in the activation of memory-related proto-oncogenes.
Topics: 3' Untranslated Regions; Carcinogenesis; Cell Line, Tumor; ELAV-Like Protein 2; Gene Expression Regulation, Neoplastic; Humans; Neoplasms; Proto-Oncogene Mas; Proto-Oncogenes; RNA, Messenger; Transcriptional Activation
PubMed: 31358321
DOI: 10.1016/j.bbrc.2019.07.089 -
The Journal of Biological Chemistry Aug 1993Hypoxic and ischemic stresses cause a series of well documented changes in myocardial cells and tissues, including increased anaerobic glycolysis, loss of contractility,...
Hypoxic and ischemic stresses cause a series of well documented changes in myocardial cells and tissues, including increased anaerobic glycolysis, loss of contractility, changes in lipid and fatty acid metabolism, and eventual irreversible membrane damage and cell death. In this article we describe changes in the expression and regulation of the proto-oncogenes fos and jun in cardiac myocytes exposed to severe hypoxia. The mRNAs encoding c-Fos, c-Jun, Jun-D, and Jun-B were induced within 1 h of exposure to hypoxia, increased 5-10-fold between 1 and 4 h and then declined. These inductions coincided with loss in myocyte contractility but occurred before there was irreversible cell damage or significant ATP loss. Immunostaining with anti-Fos and anti-Jun antibodies revealed the accumulation of these proteins in hypoxic cell nuclei. Pre-treatment of cells with protein kinase inhibitors significantly repressed the response at the mRNA level. We propose that hypoxic stress in these cells activates signal transduction pathways, possibly involving protein kinases, that result in the inductions of fos and jun gene families. Therefore AP1 may regulate myocardial adaptive responses to hypoxia in advance of energy depletion, cell damage, or reoxygenation.
Topics: Animals; Animals, Newborn; Blotting, Northern; Cell Hypoxia; Cells, Cultured; Myocardium; Protein Kinase C; Proto-Oncogene Proteins c-fos; Proto-Oncogene Proteins c-jun; Proto-Oncogenes; Rats
PubMed: 8344964
DOI: No ID Found -
British Journal of Cancer Jan 1993We examined a panel of 25 small cell lung cancer (SCLC) cell lines and nude mouse xenografts for expression of the proto-oncogenes c-met and c-kit, and for expression of...
We examined a panel of 25 small cell lung cancer (SCLC) cell lines and nude mouse xenografts for expression of the proto-oncogenes c-met and c-kit, and for expression of the corresponding ligands, hepatocyte growth factor (HGF) (also known as scatter factor (SF)), and stem cell factor (SCF), respectively. Expression of mRNA was detected by Northern blotting, and c-met and c-kit protein expression was detected by Western blotting and immunocytochemistry. c-met and c-kit mRNA was expressed in 22 of the examined cell lines or xenografts, and coexpression of the two proto-oncogenes was observed in 20 tumours. Expression of c-met and c-kit protein paralleled in the mRNA expression. HGF/SF mRNA was expressed in two of the examined tumours, and only one of these also expressed the c-met proto-oncogene. SCF mRNA was expressed in 19 of the examined tumours, and in 18 of these coexpression of c-kit and SCF was present. The high percentage of SCLC tumours expressing c-met and c-kit indicates that these proto-oncogenes may have an important function in this disease. The rare coexpression of c-met and HGF/SF is evidence that an autocrine regulatory pathway is not present for this receptor/ligand system in SCLC, while the frequent coexpression of c-kit and SCF indicates that this receptor/ligand system may have an autocrine function in SCLC.
Topics: Amino Acid Sequence; Animals; Blotting, Western; Carcinoma, Small Cell; Gene Expression; Hematopoietic Cell Growth Factors; Hepatocyte Growth Factor; Humans; Immunohistochemistry; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Sequence Data; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-kit; Proto-Oncogene Proteins c-met; Proto-Oncogenes; RNA, Messenger; Stem Cell Factor; Transcription, Genetic; Transplantation, Heterologous; Tumor Cells, Cultured
PubMed: 7678980
DOI: 10.1038/bjc.1993.7 -
BMC Genomics Dec 2018The eukaryotic unicellular protist Plasmodiophora brassicae is an endocellular parasite of cruciferous plants. In host cortical cells, this protist develops a...
BACKGROUND
The eukaryotic unicellular protist Plasmodiophora brassicae is an endocellular parasite of cruciferous plants. In host cortical cells, this protist develops a unicellular structure that is termed the plasmodium. The plasmodium is actually a multinucleated cell, which subsequently splits and forms resting spores. The mechanism for the growth of this endocellular parasite in host cell is unclear.
RESULTS
Here, combining de novo genome sequence and transcriptome analysis of strain ZJ-1, we identified top five significant enriched KEGG pathways of differentially expressed genes (DEGs), namely translation, cell growth and death, cell communication, cell motility and cancers. We detected 171 proto-oncogenes from the genome of P. brassicae that were implicated in cancer-related pathways, of which 46 were differential expression genes. Three predicted proto-oncogenes (Pb-Raf1, Pb-Raf2, and Pb-MYB), which showed homology to the human proto-oncogenes Raf and MYB, were specifically activated during the plasmodial growth in host cortical cells, demonstrating their involvement in the multinucleate development stage of the unicellular protist organism. Gene networks involved in the tumorigenic-related signaling transduction pathways and the activation of 12 core genes were identified. Inhibition of phosphoinositol-3-kinase relieved the clubroot symptom and significantly suppressed the development process of plasmodia.
CONCLUSIONS
Proto-oncogene-related regulatory mechanisms play an important role in the plasmodial growth of P. brassicae.
Topics: Amino Acid Sequence; Brassica napus; Gene Expression Profiling; Genes, myb; Genome, Protozoan; Humans; Imidazoles; Oxazepines; Plant Diseases; Plant Roots; Plasmodiophorida; Proto-Oncogene Mas; Proto-Oncogenes; Sequence Alignment; Spores, Protozoan; Transcriptome; raf Kinases
PubMed: 30522435
DOI: 10.1186/s12864-018-5307-4 -
The Tohoku Journal of Experimental... Oct 1992The myc family of proto-oncogenes encodes short-lived nuclear phosphoproteins (Myc) involved in the control of cell proliferation and differentiation. Here we discuss... (Review)
Review
The myc family of proto-oncogenes encodes short-lived nuclear phosphoproteins (Myc) involved in the control of cell proliferation and differentiation. Here we discuss the evidence for Myc's involvement in normal and abnormal cell proliferation and review recent information on Max, a novel protein that forms a sequence-specific DNA-binding complex with Myc. The properties of the Myc: Max heterodimeric complex suggest a model for how Myc may function in the cell.
Topics: Animals; Cell Division; DNA-Binding Proteins; Gene Expression Regulation; Genes, myc; Humans; Proto-Oncogene Proteins c-myc
PubMed: 1306304
DOI: 10.1620/tjem.168.195 -
Biochimica Et Biophysica Acta Jan 1995A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (> 10-fold) to several clinically active anticancer drugs,...
A variant of human prostate PC3 cells, isolated from PC3 cells, was shown to be significantly resistant (> 10-fold) to several clinically active anticancer drugs, including VP-16 and cisplatin. Previous studies showed that resistance to these drugs was not due to expression of the mdr1 gene, or modifications in topoisomerases but may have resulted from high expressions of certain proto-oncogenes (Yamazaki et al. (1994) Biochim. Biophys. Acta 1226, 89-96). Flow cytometry, DNA gel electrophoresis and northern blot analysis were used to further characterize drug responses in sensitive and resistant cells. Treatment of the sensitive PC3 cells with VP-16 and CDDP resulted in accumulation of cells in S and G2, and G1 and S phases, respectively, and caused significant degradation of the genomic DNA into internucleosomal sized DNA fragments, indicating apoptosis. In contrast, resistant PC3 cells showed little or no DNA fragmentation. Resistant PC3(R) cells expressed 2-3-fold more bcl2 protein than the parental PC3 cells, and overexpressed c-myc, c-jun and H-ras mRNA compared to sensitive cells. Treatment with VP-16 or CDDP significantly induced c-myc mRNA levels in sensitive PC3 cells. H-ras message was not affected by either VP-16 or CDDP treatment in PC3 cells. These studies, taken together, suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to altered levels of bcl2 and/or oncogene overexpression in PC3(R) cells.
Topics: Antineoplastic Agents; Apoptosis; Cell Cycle; Cisplatin; Drug Resistance; Etoposide; Gene Expression Regulation; Humans; Male; Prostatic Neoplasms; Proto-Oncogene Mas; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Proto-Oncogenes; Tumor Cells, Cultured
PubMed: 7827130
DOI: 10.1016/0925-4439(94)00065-x