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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histological and anatomopathological studies performed on 152 independent myeloblastosis-associated virus type 1 (MAV1)-induced nephroblastomas allowed us to precisely define the chronology of tumor development in chickens. Three tumors representing increasing developmental stages were used to construct genomic libraries and to study both the state of proviral genomes and the sites of MAV1 integration in genomic DNA. We established that increasing levels of proviral rearrangement, eventually leading to the elimination of infectious MAV genomes, were associated with tumor progression and that 22 individual tumors, representative of different developmental stages, did not contain any common MAV1 integration site. Cloning of cellular fragments flanking the MAV1-related proviruses in tumor DNA showed that each one of eight nephroblastomas tested expressed a high level of an as yet unidentified cellular gene (nov) whose transcription is normally arrested in adult kidney cells. Cloning of the normal nov gene established that in one tumor, fused long terminal repeat-truncated nov mRNA species were expressed, indicating that at least in that case, the high level of nov expression was under the control of the MAV long terminal repeat promoter. The normal nov gene encodes a putative 32-kDa secreted polypeptide, which is a member of a new family of proteins likely to be involved in cell growth regulation. We also showed that the expression of an amino-terminal-truncated nov product in chicken embryo fibroblasts was sufficient to induce their transformation.
Mol Cell Biol 1992 Jan
PMID:Proviral rearrangements and overexpression of a new cellular gene (nov) in myeloblastosis-associated virus type 1-induced nephroblastomas. 130 86

Although oncogenes and tumor suppressor genes have been implicated in carcinogenesis and tumor progression, their relationship to the development of genomic instability has not been elucidated. To examine this role, we transfected oncogenes (polyomavirus middle [Py] and large T [MT and LT]) and adenovirus serotype 5 E1A) into two NIH 3T3-derived cell lines, EN/NIH 2-4 and EN/NIH 2-20. Both cell lines contain two stable integrants of a variant of the retrovirus vector pZipNeoSV(x)1 that has been modified by deletion of the enhancer elements from the long terminal repeats. DNA rearrangements activating the silent neomycin phosphotransferase gene (neo) present in these integrants were identified by selection of cells in the antibiotic G418. Whereas control-transfected EN/NIH cell lines do not yield G418-resistant subclones (GRSs), a fraction of oncogene-transfected EN/NIH 2-4 (8 of 19 Py MT, 5 of 17 Py LT, and 11 of 19 E1A) and 2-20 (7 of 15 Py MT) cell lines gave rise to GRSs at differing frequencies (0.33 x 10(-6) to 46 x 10(-6) for line 2-4 versus 0.11 x 10(-6) to 1.3 x 10(-6) for line 2-20) independent of cell generation time. In contrast, a distinctly smaller fraction of mutant Py MT-transfected EN/NIH cell lines (1 of 10 MT23, 1 of 10 MT1015, and 0 of 10 MT59b) resulted in GRSs. Southern analysis of DNA from selected oncogene-transfected GRSs demonstrated genomic rearrangements of neo-containing cellular DNA that varied in type (amplification and/or novel fragments) and frequency depending on the specific oncogene and EN/NIH cell line used in transfection. Furthermore, only one of the two neo-containing genomic loci present in both EN/NIH cell lines appeared to be involved in these genomic events. In addition to effects related to the genomic locus, these observations support a role for oncogenes in the development of genetic changes associated with tumor progression.
Mol Cell Biol 1992 Jan
PMID:Oncogenes result in genomic alterations that activate a transcriptionally silent, dominantly selectable reporter gene (neo). 130 88

Cell growth and tumor transformation can be restrained in certain cell systems by the action of transforming growth factor beta (TGF-beta). It has been established that the mechanism whereby TGF-beta 1 inhibits cell growth does not interfere with the triggering of early mitogenic signal transduction mechanisms. Phospholipase C-catalyzed hydrolysis of phosphatidylcholine (PC) is a relatively late step in the cascade activated by growth factors. Therefore, conceivably activation of phospholipase C-catalyzed hydrolysis of PC could be the target of TGF-beta 1 action. In the study reported here, we demonstrate that TGF-beta 1 inhibits the coupling of ras p21 to the activation of PC hydrolysis, which appears to be critical for the antiproliferative effects of TGF-beta 1.
Mol Cell Biol 1992 Jan
PMID:Phospholipase C-mediated hydrolysis of phosphatidylcholine is a target of transforming growth factor beta 1 inhibitory signals. 130 92

Monocytes and macrophages express the receptor for the hematopoietic growth factor colony-stimulating factor 1 (CSF-1) and require this factor for growth in culture. A murine monocyte tumor cell line that lacks the usual requirement for CSF-1 was isolated. On the basis of the similarity of the structures of the CSF-1 and platelet-derived growth factor (PDGF) receptors and because monocytes normally secrete PDGF, we analyzed the tumor cell line for anomalous expression of the PDGF-R beta gene. Two different cDNAs that each contain sequences corresponding to the complete coding sequence of PDGF-R beta fused (in frame) to the amino-terminal half of the CSF-1 receptor were isolated. Introduction of these PDGF-R beta-related cDNAs into two partially transformed, CSF-1-dependent monocyte cell lines resulted in autonomous growth and cell transformation. These monocyte cell lines exhibit a novel form of growth factor receptor activation that can lead to oncogenic growth in collaboration with the c-myc oncogene.
Mol Cell Biol 1992 Jan
PMID:A colony-stimulating factor 1 (CSF-1) receptor/platelet-derived growth factor-beta receptor gene fusion confers CSF-1 independence and tumorigenicity on a c-myc-immortalized monocyte cell line. 130 94

The retinoblastoma tumor suppressor gene product (pRb) is a nuclear protein subject to cell cycle-regulated hyperphosphorylation. I constructed a recombinant vaccinia virus vector that expresses both the underphosphorylated and hyperphosphorylated forms of pRb and purified the recombinant protein by using immunoaffinity chromatography directed toward a synthetic carboxy-terminal epitope. To investigate the hypothesis that hyperphosphorylation of pRb is a means of controlling its growth-regulating activity, I tested purified pRb for the ability to be reincorporated into pRb-deficient nuclei in vitro. The underphosphorylated form of pRb efficiently reassociated with nuclei, but the hyperphosphorylated form remained soluble in this assay. Nuclear binding of pRb was enhanced by phosphatase treatment and reduced by phosphorylation of pRb effected by using a preparation of the cell cycle-regulatory kinase p34cdc2. Mutant-encoded proteins with altered E1A-binding domains failed to bind to nuclei. Pretreatment of target nuclei with nucleases and high-salt extraction did not alter the specificity of binding for underphosphorylated pRb. These observations demonstrate that hyperphosphorylation of pRb can regulate its interaction with nuclei, supporting the hypothesis that hyperphosphorylation controls the growth-regulatory activities of pRb. Further, at least one target of pRb binding appears to be an integral component of the nuclear envelope.
Mol Cell Biol 1992 Feb
PMID:Nuclear binding of purified retinoblastoma gene product is determined by cell cycle-regulated phosphorylation. 131 Jan 46

The effect of mammary gland-specific expression of the polyomavirus middle T antigen was examined by establishing lines of transgenic mice that carry the middle T oncogene under the transcriptional control of the mouse mammary tumor virus promoter/enhancer. By contrast to most transgenic strains carrying activated oncogenes, expression of polyomavirus middle T antigen resulted in the widespread transformation of the mammary epithelium and the rapid production of multifocal mammary adenocarcinomas. Interestingly, the majority of the tumor-bearing transgenic mice developed secondary metastatic tumors in the lung. Taken together, these results suggest that middle T antigen acts as a potent oncogene in the mammary epithelium and that cells that express it possess an enhanced metastatic potential.
Mol Cell Biol 1992 Mar
PMID:Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. 131 20

Irradiated mice reconstituted with bone marrow cells infected with a retrovirus carrying the bcr-abl oncogene of human chronic myeloid leukemia are subject to a range of neoplastic hematopoietic diseases, both myeloid and lymphoid. Comparison of DBA/2 and C57BL/6 mice has revealed a marked strain difference in susceptibility to the various tumor types. The present study, performed with BALB/c mice, indicates that the kinetics and nature of the induced disease can be modulated by the infection procedure, as well as the genetic background, and that retroviral regulatory sequences may influence the outcome. A distinctive clonal myeloproliferative disorder, somewhat akin to chronic myeloid leukemia but with prominent erythroid and mast cell components, as well as granulocytic excess, was characterized.
Mol Cell Biol 1992 Apr
PMID:Hematologic disease induced in BALB/c mice by a bcr-abl retrovirus is influenced by the infection conditions. 131 70

The human papillomavirus E7 gene can transform murine fibroblasts and cooperate with other viral oncogenes in transforming primary cell cultures. One biochemical property associated with the E7 protein is binding to the retinoblastoma tumor suppressor gene product (pRB). Biochemical properties associated with pRB include binding to viral transforming proteins (E1A, large T, and E7), binding to cellular proteins (E2F and Myc), and binding to DNA. The mechanism by which E7 stimulates cell growth is uncertain. However, E7 binding to pRB inhibits binding of cellular proteins to pRB and appears to block the growth-suppressive activity of pRB. We have found that E7 also inhibits binding of pRB to DNA. A 60-kDa version of pRB (pRB60) produced in reticulocyte translation reactions or in bacteria bound quantitatively to DNA-cellulose. Recombinant E7 protein used at a 1:1 or 10:1 molar ratio with pRB60 blocked 50 or greater than 95% of pRB60 DNA-binding activity, respectively. A mutant E7 protein (E7-Ala-24) with reduced pRB60-binding activity exhibited a parallel reduction in its blocking of pRB60 binding to DNA. An E7(20-29) peptide that blocks binding of E7 protein to pRB60 restored the DNA-binding activity of pRB60 in the presence of E7. Peptide E7(2-32) did not block pRB60 binding to DNA, while peptide E7(20-57) and an E7 fragment containing residues 1 to 60 partially blocked DNA binding. E7 species containing residues 3 to 75 were fully effective at blocking pRB60 binding to DNA. These studies indicate that E7 protein specifically blocks pRB60 binding to DNA and suggest that the E7 region responsible for this property lies between residues 32 and 75. The functional significance of these observations is unclear. However, we have found that a point mutation in pRB60 that impairs DNA-binding activity also blocks the ability of pRB60 to inhibit cell growth. This correlation suggests that the DNA-binding activity of retinoblastoma proteins contributes to their biological properties.
Mol Cell Biol 1992 May
PMID:Human papillomavirus type 16 E7 protein inhibits DNA binding by the retinoblastoma gene product. 131 47

Pristane is a naturally occurring isoprenoid which is believed to be derived from the phytyl moiety of chlorophyll. Thus it is not surprising that pristane is present in many common fruits or vegetables and furthermore can be detected in tissues of fish and mammals. Using the rat as an animal model, pristane can function as a potent tumor promoter. It is conceivable that pristane could play a role in the development of certain malignancies in higher mammals since it is commonly found in the diet. At the molecular level, pristane can induce changes in the plasma membrane, alter the conformation of chromatin, as well as selectively activate gene expression. This study was undertaken to identify specific transcriptional motifs which are responsive to pristane. A transcriptional promoter which contained a cAMP response element (CRE) was consistently stimulated by pristane in several mouse and primate cell lines. A promoter construct which contained a single copy of the TPA response element (TRE) was also activated by pristane but surprisingly a promoter which contained multiple copies of the TRE was not. Activation of the TRE required 10 fold higher concentrations of pristane relative to activation of the CRE. Within two hours after addition of pristane to monkey fibroblasts (CV-1) levels of cAMP were increased more than two fold relative to controls. These data indicated that pristane can increase the level of cAMP in CV-1 cells and consequently stimulate transcriptional promoters which contain a CRE.
Mol Cell Biochem 1992 Mar 04
PMID:The tumor promoter pristane activates transcription by a cAMP dependent mechanism. 131 28

The LH/CG receptor is a G protein-coupled receptor present on gonadal cells whose levels are modulated by a number of hormones, growth factors, and second messenger analogs. With the recently cloned cDNA for the LH/CG receptor, it has been shown that changes in the levels of the cognate mRNA are involved, at least in part, in the observed changes in receptor density. In order to study the transcriptional regulation of the LH/CG receptor we have isolated a 2-kilobase region of the 5'-flanking region of the rat LH/CG receptor gene and subcloned nucleotide -1 (relative to the translational initiation codon) to -1370 into a luciferase reporter plasmid. We show here that this region of the LH/CG receptor gene is able to enhance luciferase activity in MA-10 cells, a line of Leydig tumor cells that normally express LH/CG receptors, as opposed to human kidney 293 cells, which do not. Furthermore, the addition of 8-bromo-cAMP to MA-10 cells, under conditions known to decrease LH/CG receptor numbers and receptor mRNA levels, decreases the relative luciferase activity to about 26% of control. This decrease in reporter gene activity is severely blunted in a subclone of MA-10 cells with a cAMP-resistant phenotype. Our studies show, for the first time, that sequence(s) present with 1370 base pairs of the translational start site of the rat LH/CG receptor gene are sufficient for conferring expression of this gene in Leydig cells and for the negative modulation of LH/CG receptor gene transcription by high concentrations of cAMP.
Mol Endocrinol 1992 Mar
PMID:The 5'-flanking region of the rat luteinizing hormone/chorionic gonadotropin receptor gene confers Leydig cell expression and negative regulation of gene transcription by 3',5'-cyclic adenosine monophosphate. 131 38


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